# The TGF-Beta/MUC4 Signaling Axis in Circulating Tumor Cells of Metastatic Breast Cancer

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $41,568

## Abstract

PROJECT SUMMARY
Metastasis is responsible for the majority of breast cancer deaths, and standard-of-care treatments fail to
effectively target metastasizing cells. Circulating tumor cells (CTCs) in the bloodstream rely on the physical
protection and chemical signals of platelets to survive and seed metastatic lesions. One such chemical signal is
transforming growth factor beta (TGF-β), which, after secretion by platelets, has been shown to modulate CTC
gene expression and behavior. TGF-β has also been shown to upregulate expression of the cell-surface
glycoprotein Mucin-4 (MUC4) in various cellular contexts. MUC4 has been implicated in tumor development and
maintenance and was recently observed to contribute to platelet-CTC interactions. This raises the question of
whether platelet-secreted TGF-β may be upregulating CTC-MUC4, enhancing platelet-CTC interaction and
generating a positive feedback loop. The hypothesis driving the proposed studies is that platelet-TGF-β
upregulates CTC-MUC4, reinforcing CTC-platelet binding and enhancing metastatic cell survival. Specific Aim 1
will determine the effects of platelet-derived TGF-β on tumor cell MUC4 expression using cellular, molecular,
and biochemical techniques, and assess MUC4-dependent cellular aggressiveness in vitro. Specific Aim 2 will
characterize the role of MUC4 in platelet-tumor cell interactions using in vitro binding assays. Specific Aim 3 will
assess the effects of platelet-TGF-β and CTC-MUC4 crosstalk in vivo using tail vein and orthotopic xenograft
tumor mouse models of metastasis. Successful completion of this research will reveal a novel form of platelet-
CTC crosstalk, exposing an important means by which metastasizing cells survive and illuminating a potential
new therapeutic target for breast cancer metastatic prevention.

## Key facts

- **NIH application ID:** 10868446
- **Project number:** 5F31CA278419-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Savannah R Free
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,568
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868446

## Citation

> US National Institutes of Health, RePORTER application 10868446, The TGF-Beta/MUC4 Signaling Axis in Circulating Tumor Cells of Metastatic Breast Cancer (5F31CA278419-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10868446. Licensed CC0.

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