Biophysical Society Thematic Meeting| Aussois 2019

Biology and Physics Confront Cell-Cell Adhesion

Poster Abstracts

27-POS Board 27 EPITHELIAL CAVEOLIN-1 MAINTAINS MONOLAYER TENSION TO DRIVE ONCOGENIC CELL EXTRUSION Jessica Li Chang Teo 1 ; Guillermo A. Gomez 2 ; Ivar Noordstra 1 ; Suzie Verma 1 ; Vanesa Tomatis 1 ; Bipul R. Acharya 1 ; Lakshmi Balasubramaniam 3 ; Hiroko Kambe 1 ; Rachel Templin 1 ; Kerrie-Ann McMahon 1 ; Robert J. Ju 4 ; Samantha J. Stebhens 4 ; Benoit Ladoux 3 ; Robert G. Parton 1,5 ; Alpha S. Yap 1 ; 1 Division of Cell Biology and Molecular Medicine, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia 2 Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia 3 Institut Jacques Monod, CNRS, UMR 7592, Université de Paris, Paris, France 4 Translational Research Institute, The University of Queensland , Brisbane, Australia 5 Centre for Microscopy and Microanalysis, The University of Queensland, Brisbane, Australia Epithelial homeostasis and integrity are governed by cell-cell and cell-matrix adhesions. Of note, the E-cadherin-containing adherens junctions have been shown to be an important centre for mechanotransduction, by coupling the actomyosin cortices of neighbouring cells. Interestingly mechanosensitive membrane organelles, Caveolae, are found to localize near the apico-lateral region of AML12 epithelial cells where the adherens junctions reside. Caveolae have been reported to be involved in multiple biological processes such as lipid homeostasis, cellular signalling and endocytosis. However, open questions remain as to whether caveolae’s mechanosensitive nature regulates overall monolayer mechanics and what are the mechanisms involved. In this study, we report that caveolae regulate epithelial mechanics and consequently affect apical oncogenic cell extrusion. Downregulation of caveolin-1/caveolae increase tension which is detectable at the molecular, junctional and monolayer level. This increase in tension appears to be driven by an increase in PI(4,5)P2 localization at cell junctions which recruits and stabilizes the formin, FMNL2. Enrichment of FMNL2 at cell junctions led to elevated levels of junctional F-actin that are more stable and better organized. Interestingly, we found that caveolin- 1/caveolae are required to promote apical oncogenic cell extrusion in a non-cell autonomous fashion. Downregulation of caveolin-1/caveolae in the epithelium surrounding the oncogene- expressing cell reduced apical oncogenic cell extrusion. Remarkably, perturbation of the interaction between PI(4,5)P2 and FMNL2 restored monolayer tension and oncogenic cell extrusion in caveolin-1 knockdown cells. Therefore, caveolin-1/caveolae appear to regulate a PI(4,5)P2-FMNL2-actin axis to control monolayer tension and apical oncogenic cell extrusion.

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