# Uncovering Role of Exosomes in Regulating Pancreatic Cancer Cell Metabolism

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $316,861

## Abstract

PROJECT SUMMARY:
Pancreatic ductal adenocarcinoma (PDAC) is a disease of near uniform mortality, and with few tangible
therapeutic modalities. Failure of traditional therapy is due to our limited understanding of how the tumor
microenvironment (TME) can facilitate the rapid progression or recurrence of PDAC. Altered cellular
metabolism is a hallmark of cancer cells, and much of the published literature has focused on neoplastic cell
autonomous processes for these adaptations. Although cancer-associated fibroblasts (CAFs), a major
cellular component of TME, have been associated with tumor growth and metastasis through intercellular
communications with cancer cells; little is known about their role in inducing metabolic reprogramming in
cancer cells. Studies have shown that extracellular vesicles known as exosomes have emerged as a vital
communication mechanism between different cell types in the TME. Exosomes carry information from one cell
to another and reprogram the recipient cells, and recent findings report that exosomes harbor the potential to
regulate proliferation in recipient cells. Most of the current studies are focused on cancer cell secreted
exosomes; and little is known about CAF-derived exosomes (CDEs) and their metabolic influence on cancer
cells. Although it has been shown that CAFs can metabolically reprogram cancer cells, the contribution of
CDEs in this phenomenon, if any, has not been elucidated. We propose a novel regulation of cancer cell
metabolism in PDACs mediated by CDEs. First, we hypothesize that CDEs reprogram cancer cell metabolism
through miRNA based disabling of mitochondrial oxidative metabolism. Second, CDEs provide de novo “off the
shelf” metabolites through exosomal cargo to PDAC cells. We will test these hypotheses in the proposed aims.
First, to understand the underlying metabolic alterations induced by CDEs in cancer cells, we will perform 13C
GC-MS based isotope tracer analysis. To unravel the mechanism behind metabolic alterations in cancer cells
by CDEs, we will estimate the changes in metabolic gene expression in cancer cells with CDEs. Second, we
will characterize the metabolite cargo in CDEs using intra-exosomal metabolomics. We will dissect the
mechanisms by which CDEs (either indirectly through miRNAs, or directly through nutrient cargo) regulate
cancer cell metabolism. Further, we will investigate whether CDEs regulate BCAA metabolism in PDAC cells.
Third, we will establish the efficacy of CDE-mediated metabolic enrichment of cancer cells in vitro and in
mouse pancreatic tumors. We will examine the intra-exosomal metabolites contribution in enriching PDAC
cells’ proliferation. Using labeled exosomes in two distinct systems: the first, using orthotopic patient-derived
low-passage cell lines (PDCLs) and the second, using syngeneic allografts using Kras; p53 (“KPC”) murine
cells generated in a B6 background we will determine if the labeled metabolites from CDEs are being
incorporated into the tumor cel...

## Key facts

- **NIH application ID:** 9878786
- **Project number:** 5R01CA204969-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Deepak Nagrath
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,861
- **Award type:** 5
- **Project period:** 2017-03-02 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878786

## Citation

> US National Institutes of Health, RePORTER application 9878786, Uncovering Role of Exosomes in Regulating Pancreatic Cancer Cell Metabolism (5R01CA204969-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878786. Licensed CC0.

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