Blebs promote cell survival by assembling oncogenic signalling hubs

Andrew D. Weems (), Erik S. Welf, Meghan K. Driscoll, Felix Y. Zhou, Hanieh Mazloom-Farsibaf, Bo-Jui Chang, Vasanth S. Murali, Gabriel M. Gihana, Byron G. Weiss, Joseph Chi, Divya Rajendran, Kevin M. Dean, Reto Fiolka and Gaudenz Danuser ()
Additional contact information
Andrew D. Weems: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Erik S. Welf: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Meghan K. Driscoll: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Felix Y. Zhou: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Hanieh Mazloom-Farsibaf: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Bo-Jui Chang: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Vasanth S. Murali: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Gabriel M. Gihana: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Byron G. Weiss: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Joseph Chi: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Divya Rajendran: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Kevin M. Dean: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Reto Fiolka: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center
Gaudenz Danuser: Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center

Nature, 2023, vol. 615, issue 7952, 517-525

Abstract: Abstract Most human cells require anchorage for survival. Cell–substrate adhesion activates diverse signalling pathways, without which cells undergo anoikis—a form of programmed cell death1. Acquisition of anoikis resistance is a pivotal step in cancer disease progression, as metastasizing cells often lose firm attachment to surrounding tissue2,3. In these poorly attached states, cells adopt rounded morphologies and form small hemispherical plasma membrane protrusions called blebs4–11. Bleb function has been thoroughly investigated in the context of amoeboid migration, but it has been examined far less in other scenarios12. Here we show by three-dimensional imaging and manipulation of cell morphological states that blebbing triggers the formation of plasma membrane-proximal signalling hubs that confer anoikis resistance. Specifically, in melanoma cells, blebbing generates plasma membrane contours that recruit curvature-sensing septin proteins as scaffolds for constitutively active mutant NRAS and effectors. These signalling hubs activate ERK and PI3K—well-established promoters of pro-survival pathways. Inhibition of blebs or septins has little effect on the survival of well-adhered cells, but in detached cells it causes NRAS mislocalization, reduced MAPK and PI3K activity, and ultimately, death. This unveils a morphological requirement for mutant NRAS to operate as an effective oncoprotein. Furthermore, whereas some BRAF-mutated melanoma cells do not rely on this survival pathway in a basal state, inhibition of BRAF and MEK strongly sensitizes them to both bleb and septin inhibition. Moreover, fibroblasts engineered to sustain blebbing acquire the same anoikis resistance as cancer cells even without harbouring oncogenic mutations. Thus, blebs are potent signalling organelles capable of integrating myriad cellular information flows into concerted cellular responses, in this case granting robust anoikis resistance.

Date: 2023
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DOI: 10.1038/s41586-023-05758-6

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