# Mechanism of colon cancer metastasis: combined role of activin and TGF-beta signaling

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $332,601

## Abstract

PROJECT SUMMARY/ABSTRACT
Colorectal cancer (CRC) remains deadly due to metastatic disease and there is a fundamental gap in
understanding how CRC metastases form. Transforming growth factor-beta (TGFβ) promotes metastatic CRC
at later stages and TGFβ inhibitors are in early phase clinical trials, but their suboptimal performance may be
due to the lack of appreciation for its family member activin, which itself has distinct prometastatic actions. Our
preliminary studies indicate that activin and TGFβ function should be interpreted as a complexly intertwined
network and further, that tumor stroma potentiates prometastatic activin/TGFβ signaling. As activin has been
understudied in this context, the overall goal of this application is to elucidate combined prometastatic
mechanisms of activin and TGFβ signaling in CRC with a future goal of allowing metastatic risk assessment
and future niche-specific effective activin/TGFβ inhibitor-based treatments. The central hypothesis is that
activin/TGFβ trigger distinct signaling pathways that potentiate each other to promote metastatic CRC via
stromal amplification with the rationale that understanding the underlying mechanisms in individual CRC
tumors will allow risk stratification and more effective targeted treatment which minimize adverse events. This
hypothesis will be investigated with these three aims: 1) to elucidate the complementary pro-invasive actions
and cross-regulation of activin/TGFβ in CRC cells and surrounding stroma, 2) to examine the in vivo role of
activin/TGFβ signaling in CRC metastasis and 3) to fully delineate activin/TGFβ pathway status for prediction
of CRC metastasis and outcome. For this, we will use colon cancer cell models with a spectrum of
activin/TGFβ signaling status from wild type to fully abrogated with and without activin/TGFβ wild type GI
fibroblasts to assess the impact of disrupting TGFβ-induced pro-metastatic activin signaling. Our endpoints
include examination of ligand production; canonical and non-canonical effector signaling; and growth
suppression versus pro-metastatic function. To address the impact of pathway disruption in vivo, both surgical
splenic implantation and transgenic APC/KRAS murine models of CRC metastasis will be used to determine
effects of loss or augmentation of activin and TGFβ signaling or a combination thereof on liver metastasis and
outcome. Lastly, clinical implications of activin/TGFβ cross-play on metastasis and outcome in human CRC will
be examined via three complementary and comprehensive CRC cohorts. These studies are innovative as
they depart from the current dogma of single pathway assessment in TGFβ and related signaling, employ
novel techniques and models allowing integration of tumoral stromal effects and are significant, as they will
pave the way to tailored activin/TGFβ pathway and niche-specific inhibition based on individual signaling status
to target metastatic disease in CRC.

## Key facts

- **NIH application ID:** 10247095
- **Project number:** 5R01CA141057-11
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** BARBARA H JUNG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,601
- **Award type:** 5
- **Project period:** 2010-09-27 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247095

## Citation

> US National Institutes of Health, RePORTER application 10247095, Mechanism of colon cancer metastasis: combined role of activin and TGF-beta signaling (5R01CA141057-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247095. Licensed CC0.

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