# Role of extracellular matrix malleability in mediating breast cancer cell invasion and migration

> **NIH NIH R37** · STANFORD UNIVERSITY · 2024 · $329,164

## Abstract

Ductal carcinoma is the most common form of breast cancer and progresses to invasive ductal carcinoma (IDC)
when the carcinoma invades through the basement membrane (BM) into the stromal tissue. Invasion is a key
step in ductal carcinoma progression that is associated with an increased likelihood for metastasis, the most
deadly aspect of breast cancer. During metastasis, cancer cells must also invade BM during intravasation and
extravasation. The overall goal of our work is to determine how matrix mechanical plasticity (malleability)
regulates breast cancer invasion and migration. In the initial 5-year phase of this R37 award, we found that breast
cancer tissue is mechanically plastic, and that individual breast cancer cells can migrate through nanoporous
matrices independent of proteases using invadopodia if the matrix exhibits sufficient matrix mechanical plasticity.
We also found that increased covalent crosslinking of the matrix or increased stiffness inhibits invadopodia
formation, and that cancer cells can utilize filopodia to migrate along soft basement-membrane-like substrates if
the substrate is sufficiently viscoelastic or malleable. We have also pursued related lines on inquiry, finding that
extracellular matrix viscoelasticity regulates cell-cycle progression, that cancer cells generate force in order to
undergo mitotic elongation and divide in confining type-1 collagen rich matrices, that increased stiffness
regulates breast cancer progression through a YAP-independent mechanism, and that increased stiffness
induces broad changes in the epigenome that functionally mediate a stiffness-induced malignant phenotype in
mammary epithelium. While our initial studies on the role of malleability in invasion focused on single cell invasion,
initial invasion of the BM during cancer progression is thought to be collective in nature, involving the coordinated
activity of multiple cells. The specific hypothesis to be tested in this R37 extension application is that matrix
mechanical plasticity (malleability) is a key physical parameter mediates collective invasion of the BM and
subsequent migration through the type-1 collagen rich stromal matrix during cancer progression. This hypothesis
will be tested by pursuing the following two specific aims: (1) Determine how basement membrane mechanical
plasticity (malleability) mediates collective cell invasion; (2) Determine how mechanical plasticity (malleability) of
type-1 collagen rich matrices mediates collective migration of breast cancer cells. This approach is innovative
because of its focus on understanding the role of malleability in mediating protease-independent and -dependent
invasion and migration, as malleability is a physical characteristic of ECM, related to matrix viscosity but distinct
from elasticity or density, which has been largely ignored in studies to date. This work is also innovative in its
focus on collective invasion of the basement membrane instead of single cell invasion. The ...

## Key facts

- **NIH application ID:** 10789843
- **Project number:** 5R37CA214136-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Ovijit Chaudhuri
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $329,164
- **Award type:** 5
- **Project period:** 2018-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10789843

## Citation

> US National Institutes of Health, RePORTER application 10789843, Role of extracellular matrix malleability in mediating breast cancer cell invasion and migration (5R37CA214136-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10789843. Licensed CC0.

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