Plasma Membrane Blebs Induce Prosurvival Oncogenic Signaling Scaffolds

Most cell types within multicellular organisms require anchorage and undergo programmed cell death via anoikis in the absence of cell adhesion–mediated prosurvival signals, whereas cancer cells must acquire resistance to anoikis to maintain the anchorage-independent growth required for cancer progression. After detaching, normal cells typically form transient, small plasma membrane protrusions known as blebs, while cancer cells in low-adhesion environments can sustain blebbing indefinitely. To examine whether persistent blebbing may help cancer cells overcome anoikis, Weems and colleagues cultured human melanoma cell lines in nonadherent or adherent conditions and treated cells with increasing concentrations of wheat germ agglutinin to reduce plasma membrane deformability, revealing that bleb inhibition specifically induced death in detached cells. Blebbing can induce pronounced plasma membrane contours, which have been shown in other contexts to recruit septin proteins. Indeed, live-cell 3D imaging of detached melanoma cells demonstrated that sustained, bleb-generated membrane curvature was required for the recruitment of septins to the plasma membrane, and the subsequent polymerization of septin oligomers was necessary for the generation of stable septin scaffolds. Moreover, these scaffolds were important for bleb-dependent resistance to anoikis, as sustained blebbing in the context of pharmacologic septin inhibition was not sufficient for the survival of detached melanoma cells. Proximity labeling analysis revealed prominent interactions between SEPT6 and NRAS, which prompted an exploration of septin-mediated signaling through downstream NRAS effectors. Septin inhibition in detached melanoma cells reduced the spatial organization of NRAS in signaling hotspots as well as MAPK and PI3K activity, supporting the role of septins in promoting NRAS-mediated prosurvival signaling. The phenomenon of bleb- and septin-mediated resistance to anoikis appeared to be highly conserved, since sustained blebbing was sufficient to prevent anoikis upon detachment in nonmalignant mouse embryonic fibroblasts. Overall, these findings uncover a mechanism by which cancer cells endure low-adhesion environments through bleb-mediated formation of oncogenic scaffolds that maintain survival signaling and suggest that targeting bleb signaling through antiseptin drugs could improve therapeutic outcomes, including in RAS-driven tumors.

Weems AD, Welf ES, Driscoll MK, Zhou FY, Mazloom-Farsibaf H, Chang BJ, et al. Blebs promote cell survival by assembling oncogenic signalling hubs. Nature 2023;615:517–25.

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