# Regulation of collagen linearization during cancer progression and metastasis

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $402,394

## Abstract

Metastasis accounts for the vast majority of cancer-related deaths but its underlying mechanisms are
incompletely understood. During tumor progression extensive remodeling of the tumor microenvironment
occurs and facilitates metastasis. In particular, linearization of collagen, one of the most abundant extracellular
matrix (ECM) proteins in tumors, is recognized as a hallmark of aggressive breast cancers and is associated
with poor prognosis. At the cellular level, bundles of linearized collagen facilitate tumor cell invasion and
metastasis by providing tracks on which tumor cells can easily migrate. Cell-generated mechanical tension has
been proposed to contribute to collagen remodeling, but it remained unknown whether this is the sole
mechanism by which collagen linearization is established or whether other mechanisms also play prominent
roles in this process. Our recent studies revealed that cancer cells secrete factors that can linearize collagen
independently of cell-generated mechanical forces. Specifically, we found that the tumor cell-secreted factor
WISP1 (CCN4) promotes collagen linearization, tumor cell invasion and metastasis. However, the cellular and
molecular mechanisms by which WISP1 linearizes collagen and promote metastasis remain incompletely
understood. To uncover these mechanisms we will 1) define the specific steps of the metastatic cascade that
are impacted by WISP1, 2) determine the molecular mechanisms by which WISP1 regulates collagen
linearization and promotes tumor cell invasion, and 3) test therapeutic modalities to block WISP1’s function
and prevent metastasis. This will be achieved by performing detailed analyses of breast cancer progression
and metastasis in mouse models and in vitro invasion assays. Central to our studies is also the use of
scanning electron microscopy and intravital multiphoton fluorescence and second harmonic generation
microscopy to visualize alterations in ECM architecture in vitro and in vivo. Globally, these studies will elucidate
fundamental mechanisms of collagen fiber linearization and test innovative therapeutic approaches to limit
metastasis by normalizing collagen architecture.

## Key facts

- **NIH application ID:** 10219801
- **Project number:** 5R01CA245301-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Myriam Labelle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,394
- **Award type:** 5
- **Project period:** 2020-07-20 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219801

## Citation

> US National Institutes of Health, RePORTER application 10219801, Regulation of collagen linearization during cancer progression and metastasis (5R01CA245301-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10219801. Licensed CC0.

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