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.