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Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma

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Takuya Kato, Robert P Jenkins, Stefanie Derzsi, Melda Tozluoglu, Antonio Rullan, Steven Hooper, Raphaël A G Chaleil, Holly Joyce, Xiao Fu, Selvam Thavaraj, Paul A Bates, Erik Sahai

Original languageEnglish
Article numbere76520
JournaleLife
Volume12
DOIs
Accepted/In press24 Jan 2023
Published9 Mar 2023

Bibliographical note

Funding Information: We thank the Francis Crick Institute Advanced Light Microscopy facility, Cell Services, Flow Cytometry, the Biological Research facility and Experimental Histopathology facility for scientific and technical support. We thank Dr Laura Machesky for kindly providing an MMP14 plasmid. We are grateful to lab members, past and present, for help and advice throughout this work. The work was funded by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001144, FC001003), the UK Medical Research Council (FC001144, FC001003), and the Wellcome Trust (FC001144, FC001003). R.P.J., H.J., X.F., and E.S. were additionally supported by ERC Advanced Grant CAN_ORGANISE, Grant agreement number 101019366. T. K. was supported by JSPS Kakenhi grant number JP19K21262, Marie-Curie action (HeteroCancerInvasion no. 708651), The Uehara Memorial Foundation and Kitasato University Research Grant for Young Researchers. Publisher Copyright: © Kato, Jenkins et al.

King's Authors

Abstract

Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick 'pushing' collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits - no cell-cell junctions and high proteolysis - exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas.

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