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机械活性的异型E-钙黏蛋白/N-钙黏蛋白黏附作用使成纤维细胞能够驱动癌细胞侵袭。

A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion.

作者信息

Labernadie Anna, Kato Takuya, Brugués Agustí, Serra-Picamal Xavier, Derzsi Stefanie, Arwert Esther, Weston Anne, González-Tarragó Victor, Elosegui-Artola Alberto, Albertazzi Lorenzo, Alcaraz Jordi, Roca-Cusachs Pere, Sahai Erik, Trepat Xavier

机构信息

Institute for Bioengineering of Catalonia, Barcelona 08028, Spain.

The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

出版信息

Nat Cell Biol. 2017 Mar;19(3):224-237. doi: 10.1038/ncb3478. Epub 2017 Feb 20.

DOI:10.1038/ncb3478
PMID:28218910
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5831988/
Abstract

Cancer-associated fibroblasts (CAFs) promote tumour invasion and metastasis. We show that CAFs exert a physical force on cancer cells that enables their collective invasion. Force transmission is mediated by a heterophilic adhesion involving N-cadherin at the CAF membrane and E-cadherin at the cancer cell membrane. This adhesion is mechanically active; when subjected to force it triggers β-catenin recruitment and adhesion reinforcement dependent on α-catenin/vinculin interaction. Impairment of E-cadherin/N-cadherin adhesion abrogates the ability of CAFs to guide collective cell migration and blocks cancer cell invasion. N-cadherin also mediates repolarization of the CAFs away from the cancer cells. In parallel, nectins and afadin are recruited to the cancer cell/CAF interface and CAF repolarization is afadin dependent. Heterotypic junctions between CAFs and cancer cells are observed in patient-derived material. Together, our findings show that a mechanically active heterophilic adhesion between CAFs and cancer cells enables cooperative tumour invasion.

摘要

癌症相关成纤维细胞（CAFs）促进肿瘤侵袭和转移。我们发现，CAFs对癌细胞施加一种物理力，使其能够集体侵袭。力的传递是由一种异嗜性黏附介导的，这种黏附涉及CAF细胞膜上的N-钙黏蛋白和癌细胞膜上的E-钙黏蛋白。这种黏附具有机械活性；当受到力作用时，它会触发β-连环蛋白的募集和依赖于α-连环蛋白/纽蛋白相互作用的黏附增强。E-钙黏蛋白/N-钙黏蛋白黏附的受损消除了CAFs引导集体细胞迁移的能力，并阻断癌细胞侵袭。N-钙黏蛋白还介导CAFs远离癌细胞的重新极化。同时，nectins和afadin被募集到癌细胞/CAF界面，且CAF重新极化依赖于afadin。在患者来源的材料中观察到CAFs与癌细胞之间的异型连接。总之，我们的研究结果表明，CAFs与癌细胞之间具有机械活性的异嗜性黏附能够促进肿瘤的协同侵袭。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a233/5831988/7a480ef2deb5/emss-76220-f008.jpg
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