# Tissue mechanics reprograms the tissue to malignancy and metastasis

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $936,361

## Abstract

PROJECT SUMMARY
Despite breakthroughs that have improved the five-year survival of many cancer patients, the long-term
prognosis for many patients remains unchanged. My group has been studying the role of the extracellular matrix
(ECM) and tissue tension in malignant transformation and progression. Our findings argue that malignancy is
fostered by loss of tensional homeostasis induced by genetic modifications and a stiffened ECM that
synergistically stimulate actomyosins to alter the cytoskeleton, cell signaling and gene expression. This research
aims to identify conserved molecular mechanisms whereby tension promotes malignancy to identify predictive
biomarkers for risk stratification and to develop drug targets for chemoprevention and anti-tumor therapies. Our
pilot data showed a stiff ECM induces mitochondrial stress and metabolic reprogramming that promote
malignancy and tumor aggression in culture and in vivo. Studies revealed inflammation stiffens the ECM to
metabolically reprogram the myeloid cells towards a pro-tumor phenotype that represses anti-tumor immunity.
We determined that the ECM in chronically inflamed tissues with elevated risk to malignancy is stiffer and exhibits
evidence of mitochondrial stress. Thus, we predict that tissue tension induces mitochondrial stress and
compromises anti-tumor immunity to enhance tumor cell growth, survival and invasion and induce genetic
perturbations that promote malignancy and tumor aggression and foster metastasis. We have 2D and 3D culture
and mouse models with which we can measure, manipulate and modify tissue tension in breast, pancreas and
glioblastoma to test these predictions. We will expand these approaches with technical innovations that improve
analysis and monitoring of tension-dependent malignancy in vivo and our collaborators will assist with the
technical execution and clinical interpretation of the work. We have incorporated molecular and drug screens to
identify candidate regulators and inhibitory compounds to develop anti-tumor and chemoprevention treatments.

## Key facts

- **NIH application ID:** 10692813
- **Project number:** 5R35CA242447-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** VALERIE MARIE WEAVER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $936,361
- **Award type:** 5
- **Project period:** 2020-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692813

## Citation

> US National Institutes of Health, RePORTER application 10692813, Tissue mechanics reprograms the tissue to malignancy and metastasis (5R35CA242447-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692813. Licensed CC0.

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