Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly

Kazuya Tsujita,Yoshikazu Nakamura,Luis Arnes,Toshiki Itoh,Keisuke Sako,Yasuyuki Fujita,Shinobu Asada,Kiyoko Fukami,Reiko Satow

doi:10.1038/s41467-021-26156-4

Abstract

Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination. We hypothesized that the cell-intrinsic physical factors that maintain epithelial cell mechanics could function as tumor suppressors. Here we show, using optical tweezers, genetic interference, mechanical perturbations, and in vivo studies, that epithelial cells maintain higher plasma membrane (PM) tension than their metastatic counterparts and that high PM tension potently inhibits cancer cell migration and invasion by counteracting membrane curvature sensing/generating BAR family proteins. This tensional homeostasis is achieved by membrane-to-cortex attachment (MCA) regulated by ERM proteins, whose disruption spontaneously transforms epithelial cells into a mesenchymal migratory phenotype powered by BAR proteins. Consistently, the forced expression of epithelial–mesenchymal transition (EMT)-inducing transcription factors results in decreased PM tension. In metastatic cells, increasing PM tension by manipulating MCA is sufficient to suppress both mesenchymal and amoeboid 3D migration, tumor invasion, and metastasis by compromising membrane-mediated mechanosignaling by BAR proteins, thereby uncovering a previously undescribed mechanical tumor suppressor mechanism.

Highlights

Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination
This led us to hypothesize that tensional homeostasis in the plasma membrane (PM) might be an inherent mechanical feature that maintains epithelial cells in a non-motile state, with mechanisms that could function as a potent metastasis suppressor if restored in malignant cell settings
To determine whether there is a difference in PM tension between epithelial cells and their metastatic counterparts, we used optical tweezers to analyze the membrane tether force, which is proportional to PM tension[21,22,23,24] (Supplementary Fig. 1a)

Summary

Introduction

Malignancy is associated with changes in cell mechanics that contribute to extensive cell deformation required for metastatic dissemination. We show, using optical tweezers, genetic interference, mechanical perturbations, and in vivo studies, that epithelial cells maintain higher plasma membrane (PM) tension than their metastatic counterparts and that high PM tension potently inhibits cancer cell migration and invasion by counteracting membrane curvature sensing/generating BAR family proteins. Given that tense membranes resist cell membrane deformations, PM tension is assumed to disfavor the formation of any membrane protrusions[21,29,31,34] This led us to hypothesize that tensional homeostasis in the PM might be an inherent mechanical feature that maintains epithelial cells in a non-motile state, with mechanisms that could function as a potent metastasis suppressor if restored in malignant cell settings. This work paves the way for new precise therapeutic strategies for the treatment of metastatic cancers by targeting the cell membrane mechanics of cancer cells

Methods

Results

Conclusion