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Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin

In epithelia, normal cells recognize and extrude out newly emerged transformed cells by competition. This process is the most fundamental epithelial defence against cancer, whose occasional failure promotes oncogenesis. However, little is known about what factors determine the success or failure of...

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Autores principales: Pothapragada, Shilpa P., Gupta, Praver, Mukherjee, Soumi, Das, Tamal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752856/
https://www.ncbi.nlm.nih.gov/pubmed/35017535
http://dx.doi.org/10.1038/s41467-021-27896-z
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author Pothapragada, Shilpa P.
Gupta, Praver
Mukherjee, Soumi
Das, Tamal
author_facet Pothapragada, Shilpa P.
Gupta, Praver
Mukherjee, Soumi
Das, Tamal
author_sort Pothapragada, Shilpa P.
collection PubMed
description In epithelia, normal cells recognize and extrude out newly emerged transformed cells by competition. This process is the most fundamental epithelial defence against cancer, whose occasional failure promotes oncogenesis. However, little is known about what factors determine the success or failure of this defence. Here we report that mechanical stiffening of extracellular matrix attenuates the epithelial defence against HRas(V12)-transformed cells. Using photoconversion labelling, protein tracking, and loss-of-function mutations, we attribute this attenuation to stiffening-induced perinuclear sequestration of a cytoskeletal protein, filamin. On soft matrix mimicking healthy epithelium, filamin exists as a dynamically single population, which moves to the normal cell-transformed cell interface to initiate the extrusion of transformed cells. However, on stiff matrix mimicking fibrotic epithelium, filamin redistributes into two dynamically distinct populations, including a new perinuclear pool that cannot move to the cell-cell interface. A matrix stiffness-dependent differential between filamin-Cdc42 and filamin-perinuclear cytoskeleton interaction controls this distinctive filamin localization and hence, determines the success or failure of epithelial defence on soft versus stiff matrix. Together, our study reveals how pathological matrix stiffening leads to a failed epithelial defence at the initial stage of oncogenesis.
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spelling pubmed-87528562022-01-20 Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin Pothapragada, Shilpa P. Gupta, Praver Mukherjee, Soumi Das, Tamal Nat Commun Article In epithelia, normal cells recognize and extrude out newly emerged transformed cells by competition. This process is the most fundamental epithelial defence against cancer, whose occasional failure promotes oncogenesis. However, little is known about what factors determine the success or failure of this defence. Here we report that mechanical stiffening of extracellular matrix attenuates the epithelial defence against HRas(V12)-transformed cells. Using photoconversion labelling, protein tracking, and loss-of-function mutations, we attribute this attenuation to stiffening-induced perinuclear sequestration of a cytoskeletal protein, filamin. On soft matrix mimicking healthy epithelium, filamin exists as a dynamically single population, which moves to the normal cell-transformed cell interface to initiate the extrusion of transformed cells. However, on stiff matrix mimicking fibrotic epithelium, filamin redistributes into two dynamically distinct populations, including a new perinuclear pool that cannot move to the cell-cell interface. A matrix stiffness-dependent differential between filamin-Cdc42 and filamin-perinuclear cytoskeleton interaction controls this distinctive filamin localization and hence, determines the success or failure of epithelial defence on soft versus stiff matrix. Together, our study reveals how pathological matrix stiffening leads to a failed epithelial defence at the initial stage of oncogenesis. Nature Publishing Group UK 2022-01-11 /pmc/articles/PMC8752856/ /pubmed/35017535 http://dx.doi.org/10.1038/s41467-021-27896-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Pothapragada, Shilpa P.
Gupta, Praver
Mukherjee, Soumi
Das, Tamal
Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title_full Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title_fullStr Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title_full_unstemmed Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title_short Matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
title_sort matrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8752856/
https://www.ncbi.nlm.nih.gov/pubmed/35017535
http://dx.doi.org/10.1038/s41467-021-27896-z
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