Madraki, Y. | bioRxiv Science

bioRxiv2024

Tension-induced adhesion mode switching: the interplay between focal adhesions and clathrin-containing adhesion complexes

Integrin-based adhesion complexes are crucial in various cellular processes, including proliferation, differentiation, and motility. While the dynamics of canonical focal adhesion complexes (FAs) have been extensively studied, the regulation and physiological implications of the recently identified clathrin-containing adhesion complexes (CCACs) are still not well understood. In this study, we investigated the spatiotemporal mechanoregulations of FAs and CCACs in a breast cancer model. Employing single-molecule force spectroscopy coupled with live-cell fluorescence microscopy, we discovered that FAs and CCACs are mutually exclusive and inversely regulated complexes. This regulation is orchestrated through the modulation of plasma membrane tension, in combination with distinct modes of actomyosin contractility that can either synergize with or counteract this modulation. Our findings indicate that increased membrane tension promotes the association of CCACs at integrin V{beta}5 adhesion sites, leading to decreased cancer cell proliferation, spreading, and migration. Conversely, lower membrane tension promotes the formation of FAs, which correlates with the softer membranes observed in cancer cells, thus potentially facilitating cancer progression. Our research provides novel insights into the biomechanical regulation of CCACs and FAs, revealing their critical and contrasting roles in modulating cancer cell progression.

cancer biology↗

bioRxiv2022

Inhibition of Fas Receptor Endocytosis Sensitizes Cancer Cells to Fas-induced Apoptosis

The transmembrane death receptor Fas transduces apoptotic signals upon binding its ligand, FasL. Although Fas is highly expressed in cancer cells, insufficient cell surface Fas expression desensitizes cancer cells to Fas-induced apoptosis. Here, we show that the increase in Fas microaggregate formation on the plasma membrane in response to the inhibition of endocytosis sensitizes cancer cells to Fas-induced apoptosis. We used a clinically accessible Rho-kinase inhibitor, fasudil, that reduces endocytosis dynamics by increasing plasma membrane tension. In combination with exogenous soluble FasL (sFasL), fasudil promoted cancer cell apoptosis, but this collaborative effect was substantially weaker in nonmalignant cells. The combination of sFasL and fasudil prevented glioblastoma cell growth in embryonic stem cell-derived brain organoids and induced tumor regression in a xenograft mouse model. Our results demonstrate that sFasL has strong potential for apoptosis-directed cancer therapy when Fas microaggregate formation is augmented by mechano-inhibition of endocytosis.

cancer biology↗