Deciphering the Mechanotransduction Symphony:...

Deciphering the Mechanotransduction Symphony: Stiffness-Dependent Interplay of YAP and β-Catenin in Breast Cancer Metastasis

Abstract

Metastatic breast cancer poses a formidable clinical challenge, demanding a comprehensive understanding of the intricate signaling networks orchestrating disease progression. Herein, our findings revealed a pronounced increase in the nuclear translocation of both YAP and β-catenin in MDA-MB-231 cells exposed to a stiff substrate (32 kPa). Intriguingly, YAP knockdown resulted in elevated β-catenin nuclear translocation on soft substrates (2 kPa), while no significant change was observed on stiff substrates. Concurrently, the expression of Wnt/β-catenin downstream genes ( CCND1 and AXIN2) and cell migration were downregulated in MDA-MB-231 cells on stiff substrates following YAP knockdown. Conversely, on soft substrates, β-catenin nuclear localization, downstream gene expression, and cell migration remained unaltered unless both YAP and β-catenin were concurrently silenced, highlighting the compensatory role of β-catenin in response to YAP depletion in the cellular context of mechanotransduction within metastatic breast cancer cells. Moreover, our investigation revealed the significant impact of myosin-II and cell confluency on the interplay between YAP and β-catenin. Thus, we elucidated a paradigm in which β-catenin assumes a compensatory role in response to YAP knockdown, particularly under distinct mechanical conditions. The interplay is finely tuned to the mechanical microenvironment, highlighting the mechanosensitivity of this compensatory mechanism.

Authors

Geng F; Su Z; Wu Y; Ge C; Barooj S; Hirota JA

Publication date

March 10, 2024

DOI

10.22541/au.171008008.88635673/v1

Preprint server

Wiley

Associated Experts

Fei Geng

Associate Professor, Faculty of Engineering

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