# A stiffness-gated YAP-β-catenin axis orchestrates AXIN2 expression in metastatic breast cancer

## TL;DR

The study shows how the stiffness of the tumor environment influences cancer cell signaling through YAP and β-catenin, affecting gene expression in metastatic breast cancer.

## Contribution

The paper identifies a stiffness-gated YAP-β-catenin axis that regulates AXIN2 expression in a mechanical environment-dependent manner.

## Key findings

- Stiff substrates promote joint nuclear localization of YAP and β-catenin.
- AXIN2 expression requires cooperation between YAP and β-catenin, depending on matrix stiffness.
- Cytoskeletal tension and cell density modulate YAP-β-catenin signaling in response to mechanical cues.

## Abstract

Breast cancer progression is strongly influenced by the mechanical properties of the tumor microenvironment, yet how extracellular matrix stiffness coordinates signaling between YAP and β-catenin remains unclear. Using breast cancer cells cultured on soft and stiff 2D substrates and 3D Matrigel spheroids, we show that the rigid matrices drive joint nuclear localization of YAP and β-catenin, whereas compliant environments reveal a compensatory increase in β-catenin nuclear entry following YAP depletion. However, this increase is insufficient to activate canonical Wnt targets, and AXIN2 emerges as a stiffness-sensitive gene requiring cooperative input from both regulators. Cytoskeletal tension and cell density further tune this interplay, indicating that mechanical and architectural cues jointly govern nuclear signaling. In 3D culture, YAP loss reduces β-catenin nuclear localization and spheroid viability in a stiffness-dependent manner. These findings identify a mechanically gated YAP-β-catenin axis that integrates multiple microenvironmental cues to shape transcriptional programs in metastatic breast cancer.

•Stiff substrates drive coordinated nuclear translocation of YAP and β-catenin•YAP loss enhances β-catenin nuclear entry specifically on soft ECM•Cytoskeletal tension and cell density gate YAP-β-catenin mechanotransduction•AXIN2 expression requires YAP under soft conditions but becomes YAP-independent on stiff ECM

Stiff substrates drive coordinated nuclear translocation of YAP and β-catenin

YAP loss enhances β-catenin nuclear entry specifically on soft ECM

Cytoskeletal tension and cell density gate YAP-β-catenin mechanotransduction

AXIN2 expression requires YAP under soft conditions but becomes YAP-independent on stiff ECM

Mechanobiology; Cell biology; Cancer