Talk abstracts
Talk on Monday 10:05-10:20am submitted by Emily Chan
Leveraging endocytosis to sensitize cancer cells to Fas-induced apoptosis
Emily T. Chan (Biophysics Graduate Program), Umida Djakbarova, Yasaman Madraki, Valeria Arteaga Muniz, Comert Kural (Department of Physics, The Ohio State University), Bilal Cakir, Yoshiaki Tanaka, In-Hyun Park (Department of Genetics, Yale Stem Cell Center, Yale School of Medicine), Mehmet H. Kural, Hong Qian, Laura E. Niklason (Department of Anesthesiology, School of Medicine, Yale University), Jinkyu Park (Yale Cardiovascular Research Center, Department of Internal Medicine, School of Medicine, Yale University), Lorenzo R. Sewanan (Department of Internal Medicine, Columbia University)
Abstract:
Evading programmed cell death is a hallmark of cancer that allows tumor cells to survive and proliferate unchecked, promoting resistance to cytotoxic therapies. In particular, the dysregulation of Fas-mediated apoptosis in cancer cells poses a significant challenge for targeted cancer therapy. Despite the high expression of Fas receptors in cancer cells, their insufficient surface expression limits the efficacy of FasL-induced apoptosis. In this study, we investigated an approach to sensitize cancer cells to Fas-mediated apoptosis by inhibiting endocytosis through mechano-inhibition. Using the clinically accessible Rho-kinase inhibitor fasudil, we increased plasma membrane tension in cancer cells, which led to enhanced formation of Fas microaggregates on the cell surface. This increase in Fas surface density rendered cancer cells more susceptible to exogenous soluble FasL (sFasL) treatment, resulting in a reduction in cancer cell viability. Importantly, this collaborative effect was selectively observed in cancer cells, sparing nonmalignant cells. Our findings were further validated in physiologically relevant models, including 3D brain organoids and a mouse xenograft tumor model, where the combination of fasudil and sFasL demonstrated potent anti-tumor effects. Our study highlights the therapeutic potential of targeting Fas-mediated apoptosis through mechano-inhibition of endocytosis and provides insights into novel strategies for selective cancer therapy.
Keywords: cell death, endocytosis, membrane tension