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Results in Journal EMBO Molecular Medicine: 1,466

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Suzan M Hammond, , , Sven E Borgos, , , Giuseppina Covello, , Lourdes R Desviat, Lucía Echevarría, et al.
Published: 6 April 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013243

Abstract:
Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.
Jian Ma, Bowen Xing, Yan Cao, , Kate E Bennett, Chao Tong, Chiying An, Taylor Hojnacki, Zijie Feng, Sunbin Deng, et al.
Published: 6 April 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013524

Abstract:
Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)‐induced beta cell proliferation in vivo using a Pbk kinase deficiency knock‐in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin–JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD‐induced diabetic mice. Notably, Pbk is required for the MI‐induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD‐induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy.
Shalini Singh, Sourav Ghosh, Virender Kumar Pal, MohamedHusen Munshi, Pooja Shekar, Diwakar Tumkur Narasimha Murthy, ,
Published: 1 April 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013314

Abstract:
Reactive oxygen species (ROS) regulates the replication of human immunodeficiency virus (HIV‐1) during infection. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to the harmful consequences of manipulating cellular antioxidant systems. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic natural glutathione peroxidase activity to mitigate ROS associated with HIV‐1 infection without adversely affecting cellular physiology. Using genetic reporters of glutathione redox potential and hydrogen peroxide, we showed that V2O5 nanosheets catalyze ROS neutralization in HIV‐1‐infected cells and uniformly block viral reactivation and replication. Mechanistically, V2O5 nanosheets suppressed HIV‐1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g., NF‐κB), inflammation, and apoptosis. Importantly, a combination of V2O5 nanosheets with a pharmacological inhibitor of NF‐κB (BAY11‐7082) abrogated reactivation of HIV‐1. Lastly, V2O5 nanosheets inhibit viral reactivation upon prostratin stimulation of latently infected CD4+ T cells from HIV‐infected patients receiving suppressive antiretroviral therapy. Our data successfully revealed the usefulness of V2O5 nanosheets against HIV and suggested nanozymes as future platforms to develop interventions against infectious diseases.
Published: 31 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202113975

Abstract:
Many stages of the complex Plasmodium parasite life cycle, the eukaryotic pathogen that causes malaria, are extracellular and motile. This motility is essential for life cycle progression, and two studies in this issue of EMBO Molecular Medicine (Hopp et al, 2021; Ripp et al, 2021) examine the motility of two of these life cycle stages. These are the ookinete, which develops in the midgut of an infected mosquito vector, and the sporozoite, which is injected into the skin of an unsuspecting host by an infected mosquito, initiating the parasite life cycle in the human. Therapeutic targeting of the ookinete and sporozoite (Duffy & Patrick Gorres, 2020), which are profound bottlenecks in the life cycle, has recently received a great deal of attention in our battle to prevent the 400,000 deaths from malaria that occur every year (WHO, 2020).
, Hugo Abreu, Davide Raineri, Lorenza Scotti, Luigi Castello, Rosanna Vaschetto, Annalisa Chiocchetti
Published: 31 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114124

Abstract:
This study independently confirms increased levels of osteopontin in COVID-19 patients but also suggests that osteopontin cannot be used as a biomarker of SARS-CoV-2 infection, as elevated levels of circulating osteopontin are found in inflammatory lung disease regardless of SARS-CoV-2 infection.
Published: 30 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114002

Abstract:
Despite considerable efforts, therapeutic strategies targeting the Wnt pathway are still not clinically available. The pervasive role of Wnt‐βcatenin signaling for the control of stem cells during normal tissue homeostasis makes the on‐target toxicity of available therapeutic grade molecules an important limitation preventing their clinical introduction. The article in this issue of EMBO Molecular Medicine by Kaur et al (2021) reveals that treatment of Wnt‐addicted cancer cells with inhibitors of Wnt signaling induces a state of BRCAness leading to hypersensitivity to PARP inhibitors. This is a new example of induced synthetic lethality that could pave the way for new indications for PARP inhibitors or may contribute to the long‐awaited clinical introduction of therapeutic agents targeting the Wnt pathway.
Jonas Schwickert, Franziska M Zickgraf,
Published: 29 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202114010

Abstract:
Ovarian cancer has the worst prognosis of all gynecological cancers with high‐grade serous ovarian cancer (HGSOC) accounting for the majority of ovarian cancer deaths. Therapy resistance and the selection of effective therapies for patients remains a major challenge. In this issue of EMBO Molecular Medicine, Hoppe et al present RAD51 expression as a biomarker of platinum resistance in high‐grade serous ovarian cancer (HGSOC) patients (Hoppe et al, 2021).
Katja Niesel, Michael Schulz, Julian Anthes, Tijna Alekseeva, Jadranka Macas, Anna Salamero‐Boix, Aylin Möckl, Timm Oberwahrenbrock, Marco Lolies, Stefan Stein, et al.
Published: 23 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013412

Abstract:
The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer‐permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T‐cell‐directed therapies fail to elicit effective anti‐tumor immune responses. Here, we seek to evaluate the applicability of radio‐immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti‐cancer activity. Radiotherapy‐induced immune modulation resulted in an increase in cytotoxic T‐cell numbers and prevented the induction of lymphocyte‐mediated immune suppression. Radio‐immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast‐to‐brain metastasis. However, long‐term efficacy was not observed. Recurrent brain metastases showed accumulation of blood‐borne PD‐L1+ myeloid cells after radio‐immunotherapy indicating the establishment of an immune suppressive environment to counteract re‐activated T‐cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte‐derived macrophages in mediating immune suppression and regulating T‐cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio‐immunotherapy in brain metastases.
, Sachie Kanatani, Nathan K Archer, Robert J Miller, Haiyun Liu, Kevin K Chiou, Lloyd S Miller,
Published: 22 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.201911796

Abstract:
Malaria infection starts with the injection of Plasmodium sporozoites into the host’s skin. Sporozoites are motile and move in the skin to find and enter blood vessels to be carried to the liver. Here, we present the first characterization of P. falciparum sporozoites in vivo, analyzing their motility in mouse skin and human skin xenografts and comparing their motility to two rodent malaria species. These data suggest that in contrast to the liver and blood stages, the skin is not a species‐specific barrier for Plasmodium. Indeed, P. falciparum sporozoites enter blood vessels in mouse skin at similar rates to the rodent malaria parasites. Furthermore, we demonstrate that antibodies targeting sporozoites significantly impact the motility of P. falciparum sporozoites in mouse skin. Though the sporozoite stage is a validated vaccine target, vaccine trials have been hampered by the lack of good animal models for human malaria parasites. Pre‐clinical screening of next‐generation vaccines would be significantly aided by the in vivo platform we describe here, expediting down‐selection of candidates prior to human vaccine trials.
Zhili Deng, Mengting Chen, Yingzi Liu, San Xu, Yuyan Ouyang, Wei Shi, Dan Jian, Ben Wang, Fangfen Liu, Jinmao Li, et al.
Published: 18 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013560

Abstract:
Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea‐like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea‐like skin inflammation in LL37‐induced rosacea‐like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea‐like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll‐like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF‐κB activation and disease‐characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.
Arthur Gautron, Laura Bachelot, , Delphine Leclerc, Anaïs M Quéméner, , Florian Rambow, Anaïs Paris, Nina Tardif, Héloïse M Leclair, et al.
Published: 16 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013466

Abstract:
Most genetic alterations that drive melanoma development and resistance to targeted therapy have been uncovered. In contrast, and despite their increasingly recognized contribution, little is known about the non‐genetic mechanisms that drive these processes. Here, we performed in vivo gain‐of‐function CRISPR screens and identified SMAD3, BIRC3, and SLC9A5 as key actors of BRAFi resistance. We show that their expression levels increase during acquisition of BRAFi resistance and remain high in persister cells and during relapse. The upregulation of the SMAD3 transcriptional activity (SMAD3‐signature) promotes a mesenchymal‐like phenotype and BRAFi resistance by acting as an upstream transcriptional regulator of potent BRAFi‐resistance genes such as EGFR and AXL. This SMAD3‐signature predicts resistance to both current melanoma therapies in different cohorts. Critically, chemical inhibition of SMAD3 may constitute amenable target for melanoma since it efficiently abrogates persister cells survival. Interestingly, decrease of SMAD3 activity can also be reached by inhibiting the Aryl hydrocarbon Receptor (AhR), another druggable transcription factor governing SMAD3 expression level. Our work highlights novel drug vulnerabilities that can be exploited to develop long‐lasting antimelanoma therapies.
Philipp Novoszel, Martin Holcmann, Gabriel Stulnig, Cristiano De Sa Fernandes, Victoria Zyulina, Izabela Borek, Markus Linder, Alexandra Bogusch, Barbara Drobits, Thomas Bauer, et al.
Published: 16 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012409

Abstract:
Toll‐like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP‐1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c‐Jun/AP‐1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c‐Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c‐Jun in DCs or chemical blockade of JNK/c‐Jun signaling ameliorates psoriasis‐like skin inflammation by reducing IL‐23 production in DCs. Importantly, the control of IL‐23 and CCL2 by c‐Jun is most pronounced in murine type‐2 DCs. CCL2 and IL‐23 expression co‐localize with c‐Jun in type‐2/inflammatory DCs in human psoriatic skin and JNK‐AP‐1 inhibition reduces the expression of these targets in TLR7/8‐stimulated human DCs. Therefore, c‐Jun/AP‐1 is a central driver of TLR7‐induced immune responses by DCs and JNK/c‐Jun a potential therapeutic target in psoriasis.
Eleonora Maino, Daria Wojtal, Sonia L Evagelou, Aiman Farheen, Tatianna W Y Wong, Kyle Lindsay, Ori Scott, Samar Z Rizvi, Elzbieta Hyatt, Matthew Rok, et al.
Published: 16 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013228

Abstract:
Tandem duplication mutations are increasingly found to be the direct cause of many rare heritable diseases, accounting for up to 10% of cases. Unfortunately, animal models recapitulating such mutations are scarce, limiting our ability to study them and develop genome editing therapies. Here, we describe the generation of a novel duplication mouse model, harboring a multi‐exonic tandem duplication in the Dmd gene which recapitulates a human mutation. Duplication correction of this mouse was achieved by implementing a single‐guide RNA (sgRNA) CRISPR/Cas9 approach. This strategy precisely removed a duplication mutation in vivo, restored full‐length dystrophin expression, and was accompanied by improvements in both histopathological and clinical phenotypes. We conclude that CRISPR/Cas9 represents a powerful tool to accurately model and treat tandem duplication mutations. Our findings will open new avenues of research for exploring the study and therapeutics of duplication disorders.
Shan Jiang, Mathieu Richaud, Pauline Vieugué, Nicolas Rama, , Maha Siouda, Mitsuaki Sanada, Anna‐Rita Redavid, Benjamin Ducarouge, Maëva Hervieu, et al.
Published: 15 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012878

Abstract:
The navigation cue netrin‐1 is well‐documented for its key role in cancer development and represents a promising therapeutic target currently under clinical investigation. Phase 1 and 2 clinical trials are ongoing with NP137, a humanized monoclonal antibody against netrin‐1. Interestingly, the epitope recognized by NP137 in netrin‐1 shares 90% homology with its counterpart in netrin‐3, the closest member to netrin‐1 in humans, for which little is known in the field of cancer. Here, we unveiled that netrin‐3 appears to be expressed specifically in human neuroblastoma (NB) and small cell lung cancer (SCLC), two subtypes of neuroectodermal/neuroendocrine lineages. Netrin‐3 and netrin‐1 expression are mutually exclusive, and the former is driven by the MYCN oncogene in NB, and the ASCL‐1 or NeuroD1 transcription factors in SCLC. Netrin‐3 expression is correlated with disease stage, aggressiveness, and overall survival in NB. Mechanistically, we confirmed the high affinity of netrin‐3 for netrin‐1 receptors and we demonstrated that netrin‐3 genetic silencing or interference using NP137, delayed tumor engraftment, and reduced tumor growth in animal models. Altogether, these data support the targeting of netrin‐3 in NB and SCLC.
Michal M Hoppe, Patrick Jaynes, Joanna D Wardyn, Sai Srinivas Upadhyayula, , Stefanus Lie, Diana G Z Lim, Brendan N K Pang, Sherlly Lim, Joe P S Yeong, et al.
Published: 11 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013366

Abstract:
Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune‐regulatory pathways in vitro, while RAD51‐High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51‐High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
Published: 11 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013390

Abstract:
Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre‐erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well‐characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface‐expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo‐erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen‐specific CD8+ T‐cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine‐induced effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen‐specific CD8+ T‐cell killing, which has wide‐ranging implications on antigen prioritisation for next‐generation pre‐erythrocytic malaria vaccines.
Neetu Saxena, Eliana Beraldi, Ladan Fazli, Syam Prakash Somasekharan, Hans Adomat, Fan Zhang, Chidi Molokwu, Anna Gleave, Lucia Nappi, Kimberly Nguyen, et al.
Published: 11 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013427

Abstract:
Treatment‐induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration‐resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well‐known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho‐activates the AR‐cochaperone, Hsp27 via p‐CaMKK2/p‐AMPK/p‐p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient‐derived xenografts. This adaptive response is blocked by co‐targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments.
Federica Zilli, Pedro Marques Ramos, Priska Auf der Maur, Charly Jehanno, Atul Sethi, Marie‐May Coissieux, Tobias Eichlisberger, Loïc Sauteur, Adelin Rouchon, Laura Bonapace, et al.
Published: 10 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013162

Abstract:
Metastasis is the main cause of deaths related to solid cancers. Active transcriptional programmes are known to regulate the metastatic cascade but the molecular determinants of metastatic colonization remain elusive. Using an inducible piggyBac (PB) transposon mutagenesis screen, we have shown that overexpression of the transcription factor nuclear factor IB (NFIB) alone is sufficient to enhance primary mammary tumour growth and lung metastatic colonization. Mechanistically and functionally, NFIB directly increases expression of the oxidoreductase ERO1A, which enhances HIF1α‐VEGFA‐mediated angiogenesis and colonization, the last and fatal step of the metastatic cascade. NFIB is thus clinically relevant: it is preferentially expressed in the poor‐prognostic group of basal‐like breast cancers, and high expression of the NFIB/ERO1A/VEGFA pathway correlates with reduced breast cancer patient survival.
, Mitra Ebrahimpoor, Olga Veth, , Nisha Verwey, Raquel García‐Rodríguez, Christa L Tanganyika‐Dewinter, Luz B Lopez Hernandez, Rosa Escobar Cedillo, Benjamín Gómez Díaz, et al.
Published: 10 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013328

Abstract:
DMD is a rare disorder characterized by progressive muscle degeneration and premature death. Therapy development is delayed by difficulties to monitor efficacy non‐invasively in clinical trials. In this study, we used RNA‐sequencing to describe the pathophysiological changes in skeletal muscle of 3 dystrophic mouse models. We show how dystrophic changes in muscle are reflected in blood by analyzing paired muscle and blood samples. Analysis of repeated blood measurements followed the dystrophic signature at five equally spaced time points over a period of seven months. Treatment with two antisense drugs harboring different levels of dystrophin recovery identified genes associated with safety and efficacy. Evaluation of the blood gene expression in a cohort of DMD patients enabled the comparison between preclinical models and patients, and the identification of genes associated with physical performance, treatment with corticosteroids and body measures. The presented results provide evidence that blood RNA‐sequencing can serve as a tool to evaluate disease progression in dystrophic mice and patients, as well as to monitor response to (dystrophin‐restoring) therapies in preclinical drug development and in clinical trials.
Johanna Ripp, , Xanthoula Smyrnakou, Nathalie Tisch, , Rogerio Amino, ,
Published: 5 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202113933

Abstract:
Transmission of malaria‐causing parasites to and by the mosquito relies on active parasite migration and constitutes bottlenecks in the Plasmodium life cycle. Parasite adaption to the biochemically and physically different environments must hence be a key evolutionary driver for transmission efficiency. To probe how subtle but physiologically relevant changes in environmental elasticity impact parasite migration, we introduce 2D and 3D polyacrylamide gels to study ookinetes, the parasite forms emigrating from the mosquito blood meal and sporozoites, the forms transmitted to the vertebrate host. We show that ookinetes adapt their migratory path but not their speed to environmental elasticity and are motile for over 24 h on soft substrates. In contrast, sporozoites evolved more short‐lived rapid gliding motility for rapidly crossing the skin. Strikingly, sporozoites are highly sensitive to substrate elasticity possibly to avoid adhesion to soft endothelial cells on their long way to the liver. Hence, the two migratory stages of Plasmodium evolved different strategies to overcome the physical challenges posed by the respective environments and barriers they encounter.
Goetz Hartleben, Kenji Schorpp, Yun Kwon, Barbara Betz, Foivos‐Filippos Tsokanos, Zahra Dantes, Arlett Schäfer, Ina Rothenaigner, José Manuel Monroy Kuhn, Pauline Morigny, et al.
Published: 5 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012461

Abstract:
By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
Linda Scaramuzza, Giuseppina De Rocco, , Clementina Cobolli Gigli, Martina Chiacchiaretta, Filippo Mirabella, , Marco De Simone, Paola Conforti, , et al.
Published: 5 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012433

Abstract:
MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.
AmanPreet Kaur, Jun Yi Stanley Lim, Sugunavathi Sepramaniam, Siddhi Patnaik, Nathan Harmston, May Ann Lee, Enrico Petretto, ,
Published: 4 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013349

Abstract:
Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt‐addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt‐addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51, are dependent on Wnt/β‐catenin signaling in Wnt‐high cancers, and treatment with a PORCN inhibitor creates a BRCA‐like state. This coherent regulation of DNA repair genes occurs in part via a Wnt/β‐catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt‐high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/β‐catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.
Ilaria Marrocco, Donatella Romaniello, Itay Vaknin, , Roni Oren, Mary Luz Uribe, Nishanth Belugali Nataraj, Soma Ghosh, Raya Eilam, Tomer‐Meir Salame, et al.
Published: 4 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013144

Abstract:
Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti‐cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first‐, second‐, and third‐generation drugs. To explore alternatives to such whack‐a‐mole strategies, we simulated in patient‐derived xenograft models the situation of patients receiving first‐line TKIs. Monotherapies comprising approved first‐line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance‐conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next‐generation TKIs.
Julian Heuberger, Jakob Trimpert, Daria Vladimirova, Christian Goosmann, Manqiang Lin, Rosa Schmuck, Hans‐Joachim Mollenkopf, Volker Brinkmann, Frank Tacke, Nikolaus Osterrieder, et al.
Published: 3 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013191

Abstract:
SARS‐CoV‐2, the agent that causes COVID‐19, invades epithelial cells, including those of the respiratory and gastrointestinal mucosa, using angiotensin‐converting enzyme‐2 (ACE2) as a receptor. Subsequent inflammation can promote rapid virus clearance, but severe cases of COVID‐19 are characterized by an inefficient immune response that fails to clear the infection. Using primary epithelial organoids from human colon, we explored how the central antiviral mediator IFN‐γ, which is elevated in COVID‐19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS‐CoV‐2. In mouse and human colon, ACE2 is mainly expressed by surface enterocytes. Inducing enterocyte differentiation in organoid culture resulted in increased ACE2 production. IFN‐γ treatment promoted differentiation into mature KRT20+ enterocytes expressing high levels of ACE2, increased susceptibility to SARS‐CoV‐2 infection and resulted in enhanced virus production in infected cells. Similarly, infection‐induced epithelial interferon signaling promoted enterocyte maturation and enhanced ACE2 expression. We here reveal a mechanism by which IFN‐γ‐driven inflammatory responses induce a vulnerable epithelial state with robust replication of SARS‐CoV‐2, which may have an impact on disease outcome and virus transmission.
, Yuji Kiyama, Fumiko Arima‐Yoshida, , Tomoe Ichikawa, Kazuyuki Yamada, Akiko Watanabe, Hisako Ohba, Kaori Tanaka, Akihiro Nakaya, et al.
Published: 3 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012574

Abstract:
Genomic defects with large effect size can help elucidate unknown pathologic architecture of mental disorders. We previously reported on a patient with schizophrenia and a balanced translocation between chromosomes 4 and 13 and found that the breakpoint within chromosome 4 is located near the LDB2 gene. We show here that Ldb2 knockout (KO) mice displayed multiple deficits relevant to mental disorders. In particular, Ldb2 KO mice exhibited deficits in the fear‐conditioning paradigm. Analysis of the amygdala suggested that dysregulation of synaptic activities controlled by the immediate early gene Arc is involved in the phenotypes. We show that LDB2 forms protein complexes with known transcription factors. Consistently, ChIP‐seq analyses indicated that LDB2 binds to > 10,000 genomic sites in human neurospheres. We found that many of those sites, including the promoter region of ARC, are occupied by EGR transcription factors. Our previous study showed an association of the EGR family genes with schizophrenia. Collectively, the findings suggest that dysregulation in the gene expression controlled by the LDB2‐EGR axis underlies a pathogenesis of subset of mental disorders.
Christoph H Mayr, Lukas M Simon, Gabriela Leuschner, Meshal Ansari, Janine Schniering, Philipp E Geyer, Ilias Angelidis, Maximilian Strunz, Pawandeep Singh, Nikolaus Kneidinger, et al.
Published: 2 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202012871

Abstract:
The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single‐cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single‐cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type‐2 epithelial cell health status in lavage fluid and plasma. Using cross‐modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.
Oh‐Chan Kwon, Jae‐Jin Song, Yunseon Yang, Seong‐Hoon Kim, Ji Young Kim, Min‐Jong Seok, Inhwa Hwang, , Jenisha Karmacharya, Han‐Joo Maeng, et al.
Published: 1 March 2021
by EMBO
EMBO Molecular Medicine; doi:10.15252/emmm.202013076

Abstract:
Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.
, Laura Battista, Patrick Aouad, Fabio De Martino, , , , Assia Ifticene‐Treboux, Philipp Bucher, Maryse Fiche, et al.
Published: 22 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013180

Abstract:
Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E‐cadherin. It has clinical features distinct from other estrogen receptor‐positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC‐derived breast cancer cell lines, SUM‐44 PE and MDA‐MB‐134‐VI cells, into the mouse milk ducts. Using patient‐derived intraductal xenografts from lobular and non‐lobular ER+ HER2− tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell‐intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC.
Katelyn J Kozma, Susan J Done,
Published: 22 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013807

Abstract:
Invasive lobular carcinoma (ILC) of the breast is a very common disease. Despite its prevalence, these tumors are relatively understudied. One reason for this is a relative lack of models for ILC. This challenge was addressed by Brisken and colleagues through development of an intraductal injection‐based xenograft system for the study of ERα+ breast cancers, including both ILC and more common invasive ductal carcinoma (IDC; Sflomos et al, 2016). In this issue of EMBO Molecular Medicine, the same group have applied intraductal injection‐based xenografts to identify novel tumor cell‐specific transcriptional signatures in ILC (Sflomos et al, 2021). In doing so they found overexpression of lysyl oxidase‐like 1 (LOXL1) to be both responsible for the frequently seen stiff collagen‐rich extracellular matrix of lobular breast cancer and essential for their robust growth and metastatic dissemination in vivo, thereby identifying a novel therapeutic target.
Lydia Horndler, Pilar Delgado, David Abia, Ivaylo Balabanov, Pedro Martínez‐Fleta, Georgina Cornish, Miguel A Llamas, , Francisco Sánchez‐Madrid, Manuel Fresno, et al.
Published: 17 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013549

Abstract:
A correct identification of seropositive individuals for the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is of paramount relevance to assess the degree of protection of a human population to present and future outbreaks of the COVID‐19 pandemic. We describe here a sensitive and quantitative flow cytometry method using the cytometer‐friendly non‐adherent Jurkat T‐cell line that stably expresses the full‐length native spike “S” protein of SARS‐CoV‐2 and a truncated form of the human EGFR that serves a normalizing role. S protein and huEGFRt coding sequences are separated by a T2A self‐cleaving sequence, allowing to accurately quantify the presence of anti‐S immunoglobulins by calculating a score based on the ratio of fluorescence intensities obtained by double‐staining with the test sera and anti‐EGFR. The method allows to detect immune individuals regardless of the result of other serological tests or even repeated PCR monitoring. As examples of its use, we show that as much as 28% of the personnel working at the CBMSO in Madrid is already immune. Additionally, we show that anti‐S antibodies with protective neutralizing activity are long‐lasting and can be detected in sera 8 months after infection.
Marco Costantini, Stefano Testa, Ersilia Fornetti, Claudia Fuoco, Carles Sanchez Riera, Minghao Nie, Sergio Bernardini, Alberto Rainer, Jacopo Baldi, Carmine Zoccali, et al.
Published: 15 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012778

Abstract:
The importance of skeletal muscle tissue is undoubted being the controller of several vital functions including respiration and all voluntary locomotion activities. However, its regenerative capability is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. Here, we propose a biofabrication approach to rapidly restore skeletal muscle mass, 3D histoarchitecture, and functionality. By recapitulating muscle anisotropic organization at the microscale level, we demonstrate to efficiently guide cell differentiation and myobundle formation both in vitro and in vivo. Of note, upon implantation, the biofabricated myo‐substitutes support the formation of new blood vessels and neuromuscular junctions—pivotal aspects for cell survival and muscle contractile functionalities—together with an advanced muscle mass and force recovery. Altogether, these data represent a solid base for further testing the myo‐substitutes in large animal size and a promising platform to be eventually translated into clinical scenarios.
Natalija Popovic, Erika Hooker, Andrea Barabino, Anthony Flamier, Frédéric Provost, Manuel Buscarlet, ,
Published: 15 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012005

Abstract:
Neovascularization contributes to multiple visual disorders including age‐related macular degeneration (AMD) and retinopathy of prematurity. Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti‐VEGF therapies and concerns of increased risks of developing geographic atrophy following long‐term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO, a member of the Cerberus‐related DAN protein family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity. COCO equally abrogated angiogenesis in models of choroidal neovascularization. Mechanistically, COCO inhibited TGFβ and BMP pathways and altered energy metabolism and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.
Tanmoy Mondal, Gururaj N Shivange, Rachisan Gt Tihagam, Evan Lyerly, Michael Battista, Divpriya Talwar, Roxanna Mosavian, Karol Urbanek, Narmeen S Rashid, J Chuck Harrell, et al.
Published: 15 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012716

Abstract:
Lack of effective immune infiltration represents a significant barrier to immunotherapy in solid tumors. Thus, solid tumor‐enriched death receptor‐5 (DR5) activating antibodies, which generates tumor debulking by extrinsic apoptotic cytotoxicity, remains a crucial alternate therapeutic strategy. Over past few decades, many DR5 antibodies moved to clinical trials after successfully controlling tumors in immunodeficient tumor xenografts. However, DR5 antibodies failed to significantly improve survival in phase‐II trials, leading in efforts to generate second generation of DR5 agonists to supersize apoptotic cytotoxicity in tumors. Here we have discovered that clinical DR5 antibodies activate an unexpected immunosuppressive PD‐L1 stabilization pathway, which potentially had contributed to their limited success in clinics. The DR5 agonist stimulated caspase‐8 signaling not only activates ROCK1 but also undermines proteasome function, both of which contributes to increased PD‐L1 stability on tumor cell surface. Targeting DR5‐ROCK1‐PD‐L1 axis markedly increases immune effector T‐cell function, promotes tumor regression, and improves overall survival in animal models. These insights have identified a potential clinically viable combinatorial strategy to revive solid cancer immunotherapy using death receptor agonism.
, Michela Matteoli
Published: 8 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013785

Abstract:
The bidirectional link between heart and brain has intrigued scientists for ages, but little is known on the underlying mechanism. In their recent study, Fischer and colleagues (Islam et al, 2021) propose a mechanism by which heart failure‐induced cognitive decline is linked to epigenetic changes that affect gene expression in neurons of hippocampus.
Hsiang‐I Tsai, , Longshan Liu, Shengchang Xin, Yingyi Wu, Zhanxue Xu, Huanxi Zhang, Gan Liu, Zirong Bi, Dandan Su, et al.
Published: 8 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012834

Abstract:
Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter upon T‐cell activation in vitro. The elevated pre‐rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T‐cell activation can be significantly suppressed by inhibiting NF45/NF90‐dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription‐specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off‐target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90‐mediated rDNA transcription as a novel signaling pathway essential for T‐cell activation and as a new target for the development of safe and effective immunosuppressants.
Alexander C Lewis,
Published: 8 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012670

Abstract:
Altered capacity for self‐renewal and differentiation is a hallmark of cancer, and many tumors are composed of cells with a developmentally immature phenotype. Among the malignancies where processes that govern cell fate decisions have been studied most extensively is acute myeloid leukemia (AML), a disease characterized by the presence of large numbers of “blasts” that resemble myeloid progenitors. Classically, the defining properties of AML cells were said to be aberrant self‐renewal and a block of differentiation, and the term “differentiation therapy” was coined to describe drugs that promote the maturation of leukemic blasts. Notionally however, the simplistic view that such agents “unblock” differentiation is at odds with the cancer stem cell (CSC) hypothesis that posits that tumors are hierarchically organized and that CSCs, which underpin cancer growth, retain the capacity to progress to a developmentally more mature state. Herein, we will review recent developments that are providing unprecedented insights into non‐genetic heterogeneity both at steady state and in response to treatment, and propose a new conceptual framework for therapies that aim to alter cell fate decisions in cancer.
, Teemu Kuulasmaa,
Published: 8 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013720

Abstract:
Idiopathic normal pressure hydrocephalus (iNPH) is characterized clinically by degradation of gait, cognition, and urinary continence. INPH is progressive (Andrén et al, 2014), still probably underdiagnosed (Williams et al, 2019) but potentially treatable by CSF diversion (Kazui et al, 2015). Familial aggregation is a strong indicator of genetic regulation in the disease process iNPH (Fig 1). Enlargement of brain ventricles is associated with failed cerebrospinal (CSF) homeostasis by so far mostly unknown mechanisms. A mutation of the cilia gene CFAP43 in iNPH family, confirmed by a knocked‐out mouse model (Morimoto et al, 2019), allelic variation of NME8 (Huovinen et al, 2017), a segmental copy number loss in SFMBT1 in selected iNPH patients (Sato et al, 2016), and current results by Yang et al (2021) indicate that cilia dysfunction is one of the key mechanisms behind iNPH.
Annamarie E Allen,
Published: 5 February 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013568

Abstract:
Plant‐based diets exclude or substantially limit the consumption of meat and animal products and are of growing interest to many due to their sustainability and health benefits (Eshel et al, 2016). Veganism is an extreme type of plant‐based diet which excludes the consumption of all animal‐derived foods such as meat, eggs, and dairy, as well as foods containing animal‐derived ingredients. In adults, for example, certain observational studies have suggested lower body mass index, total cholesterol, LDL‐cholesterol, decreased incidence and mortality from ischemic heart disease, and decreased incidence of cancer in vegans and vegetarians versus omnivores (Dinu et al, 2017). The mechanistic basis for these observations and their generality are unclear.
, , Christopher Arico‐Muendel, Svetlana Belyanskaya, Andrew Brewster, Murray Brown, Chun‐Wa Chung, Hitesh Dave, Alexis Denis, Nerina Dodic, et al.
Published: 29 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013167

Abstract:
Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.
, , Maximilian T Strauss, Shalini Padmanabhan, Matthew Surface, Kalpana Merchant, Roy N Alcalay,
Published: 22 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013257

Abstract:
The prevalence of Parkinson's disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive, and non‐invasive biomarkers to detect PD early. Here, we describe a scalable and sensitive mass spectrometry (MS)‐based proteomic workflow for urinary proteome profiling. Our workflow enabled the reproducible quantification of more than 2,000 proteins in more than 200 urine samples using minimal volumes from two independent patient cohorts. The urinary proteome was significantly different between PD patients and healthy controls, as well as between LRRK2 G2019S carriers and non‐carriers in both cohorts. Interestingly, our data revealed lysosomal dysregulation in individuals with the LRRK2 G2019S mutation. When combined with machine learning, the urinary proteome data alone were sufficient to classify mutation status and disease manifestation in mutation carriers remarkably well, identifying VGF, ENPEP, and other PD‐associated proteins as the most discriminating features. Taken together, our results validate urinary proteomics as a valuable strategy for biomarker discovery and patient stratification in PD.
Valentina Vavassori, Elisabetta Mercuri, Genni E Marcovecchio, Maria C Castiello, Giulia Schiroli, Luisa Albano, Carrie Margulies, Frank Buquicchio, Elena Fontana, Stefano Beretta, et al.
Published: 21 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013545

Abstract:
Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X‐linked hyper‐IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one‐size‐fits‐all editing strategy for effective T‐cell correction, selection, and depletion and investigated the therapeutic potential of T‐cell and HSPC therapies in the HIGM1 mouse model. Edited patients’ derived CD4 T cells restored physiologically regulated CD40L expression and contact‐dependent B‐cell helper function. Adoptive transfer of wild‐type T cells into conditioned HIGM1 mice rescued antigen‐specific IgG responses and protected mice from a disease‐relevant pathogen. We then obtained ~ 25% CD40LG editing in long‐term repopulating human HSPC. Transplanting such proportion of wild‐type HSPC in HIGM1 mice rescued immune functions similarly to T‐cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T‐cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits.
Ningyu Zhu, ChengXian Zhang, Atish Prakash, Zheng Hou, Wei Liu, Weifeng She, Andrew Morris,
Published: 21 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012651

Abstract:
Group B Streptococcus (GBS) remains the most common Gram‐positive bacterium causing neonatal meningitis and GBS meningitis continues to be an important cause of mortality and morbidity. In this study, we showed that GBS penetration into the brain occurred initially in the meningeal and cortex capillaries, and exploits a defined host cell signaling network comprised of S1P2, EGFR, and CysLT1. GBS exploitation of such network in penetration of the blood–brain barrier was demonstrated by targeting S1P2, EGFR, and CysLT1 using pharmacological inhibition, gene knockout and knockdown cells, and gene knockout animals, as well as interrogation of the network (up‐ and downstream of each other). More importantly, counteracting such targets as a therapeutic adjunct to antibiotic therapy was beneficial in improving the outcome of animals with GBS meningitis. These findings indicate that investigating GBS penetration of the blood–brain barrier provides a novel approach for therapeutic development of GBS meningitis.
Published: 20 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013492

Abstract:
Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant‐based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years—vegans, vegetarians, or omnivores from same daycare centers—for a cross‐sectional study. They enjoyed nutritionist‐planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border‐line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n‐3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant‐onset vegan diets are warranted.
Rezaul Islam, Dawid Lbik, M Sadman Sakib, Raoul Maximilian Hofmann, Tea Berulava, Martí Jiménez Mausbach, Julia Cha, Maria Goldberg, Elerdashvili Vakhtang, Christian Schiffmann, et al.
Published: 20 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.201911900

Abstract:
In current clinical practice, care of diseased patients is often restricted to separated disciplines. However, such an organ‐centered approach is not always suitable. For example, cognitive dysfunction is a severe burden in heart failure patients. Moreover, these patients have an increased risk for age‐associated dementias. The underlying molecular mechanisms are presently unknown, and thus, corresponding therapeutic strategies to improve cognition in heart failure patients are missing. Using mice as model organisms, we show that heart failure leads to specific changes in hippocampal gene expression, a brain region intimately linked to cognition. These changes reflect increased cellular stress pathways which eventually lead to loss of neuronal euchromatin and reduced expression of a hippocampal gene cluster essential for cognition. Consequently, mice suffering from heart failure exhibit impaired memory function. These pathological changes are ameliorated via the administration of a drug that promotes neuronal euchromatin formation. Our study provides first insight to the molecular processes by which heart failure contributes to neuronal dysfunction and point to novel therapeutic avenues to treat cognitive defects in heart failure patients.
Published: 18 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012836

Abstract:
Lysosomal storage diseases are a group of metabolic disorders caused by deficiencies of several components of lysosomal function. Most commonly affected are lysosomal hydrolases, which are involved in the breakdown and recycling of a variety of complex molecules and cellular structures. The understanding of lysosomal biology has progressively improved over time. Lysosomes are no longer viewed as organelles exclusively involved in catabolic pathways, but rather as highly dynamic elements of the autophagic‐lysosomal pathway, involved in multiple cellular functions, including signaling, and able to adapt to environmental stimuli. This refined vision of lysosomes has substantially impacted on our understanding of the pathophysiology of lysosomal disorders. It is now clear that substrate accumulation triggers complex pathogenetic cascades that are responsible for disease pathology, such as aberrant vesicle trafficking, impairment of autophagy, dysregulation of signaling pathways, abnormalities of calcium homeostasis, and mitochondrial dysfunction. Novel technologies, in most cases based on high‐throughput approaches, have significantly contributed to the characterization of lysosomal biology or lysosomal dysfunction and have the potential to facilitate diagnostic processes, and to enable the identification of new therapeutic targets.
Hong Wei Yang, Semin Lee, Dejun Yang, Huijun Dai, Yan Zhang, Lei Han, Sijun Zhao, Shuo Zhang, Yan Ma, Marciana F Johnson, et al.
Published: 18 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202013249

Abstract:
Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that occurs in about 1% of individuals over age 60 and is characterized by enlarged cerebral ventricles, gait difficulty, incontinence, and cognitive decline. The cause and pathophysiology of iNPH are largely unknown. We performed whole exome sequencing of DNA obtained from 53 unrelated iNPH patients. Two recurrent heterozygous loss of function deletions in CWH43 were observed in 15% of iNPH patients and were significantly enriched 6.6‐fold and 2.7‐fold, respectively, when compared to the general population. Cwh43 modifies the lipid anchor of glycosylphosphatidylinositol‐anchored proteins. Mice heterozygous for CWH43 deletion appeared grossly normal but displayed hydrocephalus, gait and balance abnormalities, decreased numbers of ependymal cilia, and decreased localization of glycosylphosphatidylinositol‐anchored proteins to the apical surfaces of choroid plexus and ependymal cells. Our findings provide novel mechanistic insights into the origins of iNPH and demonstrate that it represents a distinct disease entity.
Xinyuan Tong, Yueqing Chen, Xinsheng Zhu, Yi Ye, Yun Xue, Rui Wang, Yijun Gao, Wenjing Zhang, Weiqiang Gao, Lei Xiao, et al.
Published: 13 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012627

Abstract:
Growing evidence supports that LKB1‐deficient KRAS‐driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL‐G12D/+; Lkb1flox/flox (KL) model show strong plasticity, which associates with up‐regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ‐secretase inhibitor LY‐411575 remarkably impairs mucinous tumor formation. In contrast to non‐mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY‐411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1‐deficient tumors and identify the Nanog‐Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.
Subhrangshu Guhathakurta, Jinil Kim, Levi Adams, Sambuddha Basu, Min Kyung Song, Evan Adler, Goun Je, Mariana Bernardo Fiadeiro,
Published: 11 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012188

Abstract:
Epigenetic deregulation of α‐synuclein plays a key role in Parkinson’s disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone post‐translational modifications (PTMs) including transcription‐promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in post‐mortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy and in NeuN‐positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α‐synuclein, we developed CRISPR/dCas9‐based locus‐specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag‐JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α‐synuclein both in the neuronal cell line SH‐SY5Y and idiopathic PD‐iPSC derived dopaminergic neurons. In sum, this study indicates that α‐synuclein expression in PD is controlled by SNCA’s histone PTMs and modulation of the histone landscape of SNCA can reduce α‐synuclein expression.
Mihyun Bae, Junyeop Daniel Roh, Youjoung Kim, Seong Soon Kim, Hye Min Han, Esther Yang, Hyojin Kang, Suho Lee, , Ryeonghwa Kang, et al.
Published: 11 January 2021
by EMBO
EMBO Molecular Medicine, Volume 13; doi:10.15252/emmm.202012632

Abstract:
Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.
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