Science Signaling

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ISSN / EISSN : 19450877 / 19379145
Total articles ≅ 12,137
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Quentin Defenouillère, Agathe Verraes, Clotilde Laussel, Anne Friedrich, Joseph Schacherer, Sébastien Léon
Science Signaling, Volume 12; doi:10.1126/scisignal.aaw8000

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Jamie C. Fox, Monica A. Thomas, Acacia F. Dishman, Olav Larsen, Takashi Nakayama, Osamu Yoshie, Mette Marie Rosenkilde, Brian F. Volkman
Science Signaling, Volume 12; doi:10.1126/scisignal.aat4128

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Brenal K. Singh, Wen Lu, Amanda M. Schmidt Paustian, Moyar Q. Ge, Cynthia J. Koziol-White, Cameron H. Flayer, Sara S. Killingbeck, Nadan Wang, Xinzhong Dong, Matthew J. Riese, et al.
Science Signaling, Volume 12; doi:10.1126/scisignal.aax3332

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John F. Foley
Science Signaling, Volume 12; doi:10.1126/scisignal.aaz3175

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John Rizk, Joseph Kaplinsky, Rasmus Agerholm, Darshana Kadekar, Fredrik Ivars, William W. Agace, W. Wei-Lynn Wong, Matthew J. Szucs, Samuel A. Myers, Steven A. Carr, et al.
Science Signaling, Volume 12; doi:10.1126/scisignal.aaw3469

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Jai Rautela, Laura F. Dagley, Carolina C. De Oliveira, Iona S. Schuster, Soroor Hediyeh-Zadeh, Rebecca B. Delconte, Joseph Cursons, Robert Hennessy, Dana S. Hutchinson, Craig Harrison, et al.
Science Signaling, Volume 12; doi:10.1126/scisignal.aat7527

Abstract:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor–β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)–dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD2/3 to suppress IL-15–mediated NK cell metabolism. Activin-A impaired human and mouse NK cell proliferation and reduced the production of granzyme B to impair tumor killing. Similar to TGF-β, activin-A also induced SMAD2/3 phosphorylation and stimulated NK cells to increase their cell surface expression of several markers of ILC1 cells. Activin-A also induced these changes in TGF-β receptor–deficient NK cells, suggesting that activin-A and TGF-β stimulate independent pathways that drive SMAD2/3-mediated NK cell suppression. Last, inhibition of activin-A by follistatin substantially slowed orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-β–independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.
Stephanie K. Dougan, Michael Dougan
Science Signaling, Volume 12; doi:10.1126/scisignal.aay3986

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Leslie K. Ferrarelli
Science Signaling, Volume 12; doi:10.1126/scisignal.aaz1991

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SreeHarsha Gurrapu, Giulia Franzolin, Damon Fard, Massimo Accardo, Enzo Medico, Ivana Sarotto, Anna Sapino, Claudio Isella, Luca Tamagnone
Science Signaling, Volume 12; doi:10.1126/scisignal.aav2041

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Aaron Goldman, Sachin Khiste, Elizaveta Freinkman, Andrew Dhawan, Biswanath Majumder, Jayanta Mondal, Anthony B. Pinkerton, Elliot Eton, Ragini Medhi, Vineethkrishna Chandrasekar, et al.
Science Signaling, Volume 12; doi:10.1126/scisignal.aas8779

Abstract:Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44Hi) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44Hi phenotype to increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP). When given in a specific order, a combination of taxanes, anthracyclines, and inhibitors of glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in glucose metabolism, improved survival in mouse models of breast cancer. The same sequence of the three-drug combination reduced the viability of patient breast tumor samples in an explant system. Our findings highlight a convergence between phenotypic and metabolic state transitions that confers a survival advantage to cancer cells against clinically used drug combinations. Pharmacologically targeting this convergence could overcome cross-drug tolerance and could emerge as a new paradigm in the treatment of cancer.