# A physical sciences approach to investigate the role of exosomes in metastatic progression

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $659,220

## Abstract

Project Summary:
 Metastatic cancer is a major clinical challenge that accounts for numerous deaths annually in the United
States, particularly in women with triple-negative breast cancer (TNBC). Many tumors develop within a
microenvironment (TME) characterized by altered/stiffened extracellular matrix (ECM) and compromised
immunity. These alterations play a causal role in malignancy and metastasis. Recently tumor-derived exosomes
have drawn tremendous interest as they are implicated in modulating the TME, suppressing anti-tumor immunity,
and preparing the metastatic site for progression. A hallmark of cancer cells is their ability to evade the immune
system. Exosomes play a pivotal role in the suppression of anti-tumor immunity. In this project, focusing on
TNBC, we explore how ECM stiffness and cytoskeletal tension (collectively referred to as tissue tension) regulate
exosome production and cargo composition, and how these exosomes contribute to the suppression of anti-
tumor immunity and promote metastasis. We pursue a unique set of hypotheses linking tissue tension to
exosome production and defining the role of tumor-derived exosomes in immune surveillance and metastatic
progression. To test our hypotheses, we have assembled a strong team from UPENN and UCSF, integrating
expertise in bioengineering, cancer mechanobiology, and cancer immunology. In Aim 1, we address whether
and how the tissue tension affects exosome production and alters exosome cargo in vitro in TNBC cells. We will
also delineate a molecular pathway linking ECM stiffness to intracellular signaling and exosome trafficking, using
experimental and subcellular biophysical modeling methods. In Aim 2, we address how tissue tension promotes
metastatic progression via exosomes in vivo. In this aim we test the hypothesis that the tension of the primary
tumor tissue enhances exosome production and alters exosome cargo to promote the dissemination of primary
tumor cells and foster their survival and outgrowth at the metastatic site. We will use unique genetically
engineered mouse models (GEMMs) and syngeneic TNBC models, and TNBC patient PDXs, combined with
multiscale pharmacokinetic modeling. In Aim 3, we address how tissue tension contributes to the suppression of
anti-tumor immunity. In this aim, we will investigate the role of exosomes derived from tumors with high tension
in stiff ECM TMEs in suppressing anti-tumor immunity through (1) reprogramming macrophages against T cells;
and (2) the engagement of PD-1/PD-L1 checkpoint axis in T cells. We will use a combination of in vitro cell
culture experiments, in vivo genetically engineered mouse models and syngeneic transplant manipulations and
tissue-scale agent-based modeling. The expected results will shed light on the roles of exosomes in immune
regulation and metastatic tumor progression; these are important and timely questions in cancer research. The
results will lay the foundation for future therapeutic intervention of metastati...

## Key facts

- **NIH application ID:** 10489753
- **Project number:** 5U01CA250044-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** WEI GUO
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $659,220
- **Award type:** 5
- **Project period:** 2021-09-16 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489753

## Citation

> US National Institutes of Health, RePORTER application 10489753, A physical sciences approach to investigate the role of exosomes in metastatic progression (5U01CA250044-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489753. Licensed CC0.

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