# Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $356,497

## Abstract

Breast tumors are often identified by manual palpation due to their apparent “hardness” compared to normal
tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue
stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix
stiffness can induce a malignant phenotype in cultured human mammary organoids, suggesting that
mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical
forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown.
Our preliminary studies found that rigid matrix stiffness activates a novel mechanotransduction pathway to
induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We therefore hypothesize
that mechanical forces activates the LYN kinase to allow the EMT-inducing transcription factor TWIST1 to
promote tumor invasion and metastasis. To test this hypothesis, we plan to 1) To elucidate the molecular
mechanism by which high tissue stiffness activates a novel mechanotransduction cascade to promote TWIST1
nuclear translocation and EMT; 2) To elucidate the novel molecular mechanism by which soft matrix stiffness
prevents TWIST1 nuclear translocation and inhibit EMT; 3) To determine the involvement of the Twist1
mechanotransduction pathway in promoting metastasis in vivo and in predicting human breast cancer
progression.

## Key facts

- **NIH application ID:** 10557145
- **Project number:** 5R01CA174869-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jing Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $356,497
- **Award type:** 5
- **Project period:** 2015-08-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10557145

## Citation

> US National Institutes of Health, RePORTER application 10557145, Regulation of Tumor Invasion and Metastasis by Matrix Stiffness (5R01CA174869-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10557145. Licensed CC0.

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