Cancer Research

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ISSN / EISSN : 0008-5472 / 1538-7445
Total articles ≅ 55,690
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Dragana Kopanja, , Eilidh Mills. O'Brien, Nishit K. Mukhopadhyay, Maria Paula. Zappia, , , Bradley J. Merrill,
The transcription factor Forkhead box M1 (FoxM1) is overexpressed in breast cancers and correlates with poor prognosis. Mechanistically, FoxM1 associates with CBP to activate transcription and with Rb to repress transcription. While the activating function of FoxM1 in breast cancer has been well documented, the significance of its repressive activity is poorly understood. Using CRISPR-Cas9 engineering, we generated a mouse model that expresses FoxM1 harboring point mutations that block binding to Rb while retaining its ability to bind CBP. Unlike FoxM1-null mice, mice harboring Rb-binding mutant FoxM1 did not exhibit significant developmental defects. The mutant mouse line developed PyMT-driven mammary tumors that were deficient in lung metastasis, which was tumor cell-intrinsic. Single-cell RNA-seq of the tumors revealed a deficiency in pro-metastatic tumor cells and an expansion of differentiated alveolar-type tumor cells, and further investigation identified that loss of the FoxM1/Rb interaction caused enhancement of the mammary alveolar differentiation program. The FoxM1 mutant tumors also showed increased Pten expression, and FoxM1/Rb was found to activate Akt signaling by repressing Pten. In human breast cancers, expression of FoxM1 negatively correlated with Pten mRNA. Furthermore, the lack of tumor-infiltrating cells in FoxM1 mutant tumors appeared related to decreases in pro-metastatic tumor cells that express factors required for infiltration. These observations demonstrate that the FoxM1/Rb-regulated transcriptome is critical for the plasticity of breast cancer cells that drive metastasis, identifying a pro-metastatic role of Rb when bound to FoxM1.
Shawn M. Davdison, , Julia E. Heyman, James P. O'Brien, Amy C. Liu, , Talya L. Dayton, Raghav Sehgal, Roderick T. Bronson, Elizaveta Freinkman, et al.
Altered metabolisms helps sustain cancer cell proliferation and survival. Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2), which can support anabolic metabolism to support cell proliferation. However, Pkm2 expression is dispensable for the formation and growth of many cancers in vivo. Expression of pyruvate kinase isoform M1 (Pkm1) is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of Pkm1 in cancer has been less studied than Pkm2. To test how differential expression of pyruvate kinase isoforms affects cancer initiation and progression, we generated mice harboring a conditional allele of Pkm1, and crossed these mice or those with a Pkm2 conditional allele with a Pten loss-driven prostate cancer model. Pkm1 loss led to increased Pkm2 expression and accelerated prostate cancer development, while Pkm2 deletion of led to increased Pkm1 expression and suppressed tumor progression. Metabolic profiling revealed altered nucleotide levels in tumors with high Pkm1 expression, and failure of these tumors to progress was associated with DNA replication stress and senescence. Consistent with these data, a small molecule pyruvate kinase activator that mimics a high activity Pkm1-like state suppressed progression of established prostate tumors. Analysis of human specimens showed PKM2 expression is retained in most human prostate cancers. Overall, this study uncovers a role for pyruvate kinase isoforms in prostate cancer initiation and progression, and argues that pharmacological pyruvate kinase activation may be beneficial for treating prostate cancer.
Amrita M. Nargund, Chang Xu, Amit Mandoli, Atsushi Okabe, Gao Bin Chen, Kie Kyon Huang, Taotao Sheng, Xiaosai Yao, Jia Ming Nickolas Teo, , et al.
Mutations in the DNA mismatch repair gene MSH2 are causative of microsatellite instability (MSI) in multiple cancers. Here, we discovered that besides its well-established role in DNA repair, MSH2 exerts a novel epigenomic function in gastric cancer (GC). Unbiased CRISPR-based mass spectrometry combined with genome-wide CRISPR functional screening revealed that in early-stage GC MSH2 genomic binding is not randomly distributed but rather is associated specifically with tumor-associated super-enhancers controlling the expression of cell adhesion genes. At these loci, MSH2 genomic binding was required for chromatin rewiring, de novo enhancer-promoter interactions, maintenance of histone acetylation levels, and regulation of cell adhesion pathway expression. The chromatin function of MSH2 was independent of its DNA repair catalytic activity but required MSH6, another DNA repair gene, and recruitment to gene loci by the SWI/SNF chromatin remodeler SMARCA4/BRG1. Loss of MSH2 in advanced GCs was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient GCs also displayed addiction to BAZ1B, a bromodomain-containing family member, and consequent synthetic lethality to bromodomain and extra-terminal motif (BET) inhibition. Our results reveal a role for MSH2 in GC epigenomic regulation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies.
, Hong Cao, , Le Han, Ruoqi Wang, Rosel Blasig, Reiner Haseloff, Yue Qin, Jie Lan, Xiaohan Lou, et al.
Migration of myeloid-derived suppressor cells (MDSCs) out of the circulation, across vascular walls, and into tumor is crucial for their immunosuppressive activity. A deeper understanding of critical junctional molecules and the regulatory mechanisms that mediate the extravasation of MDSCs could identify approaches to overcome cancer immunosuppression. In this study we used mice deficient in tight-junction protein Claudin-12 (Cldn12) compared to wild-type mice and found that loss of host Cldn12 inhibited the growth of transplanted tumors, reduced intratumoral accumulation of MDSCs, increased anti-tumor immune responses, and decreased tumor vescular density. Further studies revealed that Cldn12 expression on the cell surface of both MDSCs and endothelial cells is required for MDSCs transit across tumor vascular endothelial cells (ECs). Importantly, expression of Cldn12 in MDSCs was modulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in an AKT-dependent manner. Therefore, our results indicate that Cldn12 could serve as a promising target for restoring the anti-tumor response by interfering with MDSCs transendothelial migration.
Dong-E Tang, Jia-Xi He, Yong Dai, Hui-Fen Zhou, Cancan Zhang, Qi-Xin Leng, Xinyan Geng, Dexue Fu, Hao-Wu Jiang, Rui Sun, et al.
The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer (PCa). Specific homozygous deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the homozygous loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly up-regulated in PCa and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed PCa growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance.
Cancer Research, Volume 82, pp 1870-1871;

The invasive progression of cancer known as metastasis remains strongly associated with morbidity and lethality. New meaningful therapeutic interventions could be derived from a better understanding of the underlying processes driving cancer cell seeding and proliferation at secondary sites. Emerging findings regarding the heterogeneity of cancer cells observed in metastases have led us to revisit concepts surrounding metastatic fitness. Novel model systems to study the markers of cancer stem cell plasticity and their evolution during metastatic growth have uncovered that dynamic and heterogeneous cancer cell populations are observed during metastatic disease progression. Heinz and colleagues studied the heterogeneity of colorectal carcinomas, where primary tumors evolve alongside an epithelium well characterized for its self-renewing stem cell population. Their work revealed a functional dynamic interplay in the organization of the metastatic lesions as they transition from stagnating to expanding nodules, wherein the heterogeneous mixture of cancer cell stem cells with more differentiated cancer cells is essential for metastatic outgrowth. Their work supports that dynamic YAP signaling enables the growth-permissive heterogeneous composition of the metastatic nodule, in contrast with growth-restricted homogeneous compositions. See related article by Heinz et al., p. 1953
Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, et al.
Despite recent advances in the treatment of advanced melanoma using immune checkpoint inhibitors (ICI), 5-year overall survival remains suboptimal. A clear understanding of the potential evolutionary trajectories of melanoma is needed in order to advance treatment and prognostic options. Here we present the Posthumous Evaluation of Advanced Cancer Environment (PEACE) study of advanced melanoma, revealing a diversity of evolutionary pathways to lethality. This interim analysis of our 50-patient cohort comprises 14 ICI-treated patients with a mixture of phenotypic subtypes, including cutaneous, acral, mucosal and melanoma of unknown primary. The sampling regime encompasses a broad range of visceral metastases from various organ sites, with a total of 573 tumor samples (an average of 40 samples per patient). Our data span a variety of modalities, including exomic, transcriptomic, panel sequencing, single cell sequencing, FISH, and radiological data. Clonal phylogenies of patients were diverse in structure: some followed a linear evolutionary trajectory with little to no branching, whereas others followed a branched evolutionary pattern. We also observed various patterns of metastatic seeding, with both monoclonal and polyclonal cases of seeding. In addition, patients treated with chemotherapy showed higher subclonal mutational burden than those without. As with previous literature, we found extensive copy number alterations in these advanced melanomas. In contrast, however, our data also reveal patients with no incidence of WGD, with previous work finding this to be a ubiquitous feature of advanced melanoma. In cases of WGD, the majority of copy number alterations were losses rather than gains. In terms of treatment resistance, we observed loss of heterozygosity in key genes of the antigen presentation pathway (most notably B2M), and little signal of neoantigen loss via immunoediting, indicating that these tumors develop resistance to ICI regardless of neoantigen burden. A further question of interest was the determination of lesion-level factors influencing response to ICI treatment using radiological data. MYC amplification was significantly associated with non-responding lesions, whilst PBX1, a promoter of natural killer cells, was shown to be significantly amplified in responding lesions. Our single-cell data reveal a case of polyclonal seeding at the level of whole-genome doubling. This has implications for sample-level phylogenies that are inferred from copy-number status, indicating that intra-tumor heterogeneity at the level of copy number could confound these trees. We also find a potentially novel driver of melanoma, PHF3. This gene has previously been associated with UV DNA-damage response, however here it was found in a non-sun damaged melanoma to have a clonal, focal 7n copy number gain in an otherwise diploid cancer, with corresponding upregulation of expression. In summary, our study comprises an extensive intra-patient, multi-lesion analysis of advanced melanoma, with important implications in both technical and clinical settings. Citation Format: Alexander Coulton, Irene Lobon, Lavinia Spain, Andrew Rowan, Desiree Shnidrig, Scott Shepherd, Ben Shum, Fiona Byrne, Lewis Au, Kim Edmonds, Ellie Carlyle, Alexandra Renn, Christina Messiou, Charlotte Spencer, Andreas M. Schmidt, Zayd Tippu, Aljosja Rogiers, Max Emmerich, Camille Gerard, Husayn Pallikonda, Cristina Naceur-Lombardelli, Floris Foijer, Hilda van den Bos, René Wardenaar, Diana Spierings, Kate Young, Lisa Pickering, Andrew Furness, Elaine Borg, Miriam Mitchison, David Moore, Mary Falzon, Ian Proctor, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Charles Swanton, Mariam Jamal-Hanjani, Kevin Litchfield, Samra Turajlic. Advanced melanoma exhibits a diversity of evolutionary routes to lethality [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR002.
Rachael M. Giersch, Marisa A. Yonemitsu, Samuel F.M. Hart, Michael J. Metzger
This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR017) of the Conference Proceedings. Citation Format: Rachael M. Giersch, Marisa A. Yonemitsu, Samuel F.M. Hart, Michael J. Metzger. Progression and regression dynamics of bivalve transmissible neoplasia in the soft-shell clam (Mya arenaria) after both natural and experimental exposure [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A023.
Robert Vander Velde, Sydney Shaffer
Targeted therapies provide substantial benefits to cancer patients by shrinking and controlling tumors. However, the long-term efficacy of targeted therapy is limited by the development of resistance. Once a tumor is fully resistant, it continues to grow despite the presence of the targeted therapy, leading to disease relapse in the patient. When the therapy is first applied, a number of studies have now shown that there is initially a selection for cells that are able to tolerate the drug (termed “tolerant cells”). This contrasts with selection of fully resistant cells. More recently our studies have suggested that the transition from tolerance to resistance is not binary and involves multiple changes. These changes can be propelled by the stochastic generation of heritable heterogeneity followed by selection (Darwinian evolution), by long-term changes in signaling networks (reprogramming) and by combinations of these two. The contribution of these factors determines the usefulness of strategies using either evolutionary dynamics (such as reducing population size or changing selective pressures on tumor cells) or therapies that alter cell states (such as inhibiting or activating key signaling nodes). We are using colony assays and developing barcoding techniques to address the role of selection and clonality in the evolution of full resistance to BRAF inhibitors in melanoma from a tolerant state. Early results show a rapid increase in fitness (relative to surviving tolerant cells) suggesting a role for selection immediately after the first selective event. These changes are followed by slow changes that may be the result of mostly reprogramming. This implies that strategies that manipulate evolutionary dynamics are most effective early in resistance evolution while later changes can be manipulated by altering signaling nodes. Citation Format: Robert Vander Velde, Sydney Shaffer. Selection and reprogramming contribute to the evolution of targeted therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B016.
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