# Metabolism of Extracellular Matrix Supports Pancreatic Cancer Growth

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $39,007

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) has the worst five-year survival rate of any major cancer. The lethality
of PDA is largely due to lack of effective treatment options. A major obstacle in PDA treatment is conferred by
the tumor microenvironment, composed mainly of dense fibroinflammatory stromal response. The stroma is
populated mainly by immune cells and cancer-associated fibroblasts (CAF). CAFs deposit extensive extracellular
matrix components, including a high degree of hyaluronic acid (HA). HA is a ubiquitous, hydrophilic carbohydrate
polymer. The high HA levels in PDA tumors retain water, leading to supraphysiological interstitial pressure. The
high pressure collapses the vasculature, limiting drug penetrance, and oxygen and nutrient availability.
To sustain viability in the austere microenvironment, cancer cells undergo metabolic reprogramming via mutant
Kras, the signature transforming oncogene in PDA. Mutant Kras enhances flux through the hexosamine
biosynthesis pathway (HBP) by regulating the rate-limiting enzyme glutamine-fructose 6-phosphate
transamidase (GFAT). The HBP is a highly conserved pathway that integrates glucose and glutamine
metabolism. In addition, the HBP is the only way to synthesize glycosylation substrate de novo. Therefore, the
HBP represents an attractive therapeutic target in PDA.
In contrast to this necessary role, my preliminary data show that the HBP is not an effective therapeutic target in
vivo. Rather, I found that cancer cells are able to utilize HA, a carbohydrate polymer, to fuel the HBP and support
growth independent of its activity. My data illustrate that one of the ways cancer cells achieve this is by utilizing
N-acetyl-glucosamine (GlcNAc) from HA via GlcNAc salvage pathway. The data implicate HA as a novel nutrient
source for cancer cells. They also point to a novel metabolic reprogramming that cancer cells undergo to survive
and proliferate in the nutrient-poor tumor microenvironment.
The working hypothesis of this proposal is that CAFs support PDA metabolism via the release of GlcNAc as HA.
This will be examined in two parts. First, mechanistic studies involving genetic and pharmacological inhibition of
HA synthesis by CAF and HA uptake by cancer cells will be performed; functional consequences of targeting
these features will be defined in vitro and in vivo (Specific Aim 1). Second, mechanistic studies involving genetic
inhibition of HA catabolism and GlcNAc salvage pathway will be performed; similarly, the functional
consequences of targeting these pathways will be defined in vitro and in vivo (Specific Aim 2). The in vitro studies
will be performed on a patient-derived CAF and human PDA cell lines. Further, I will demonstrate the role for
this pathway using orthotopic co-injection in vivo studies with genetically-modified CAF and PDA cells . This
proposal aims to functionally and mechanistically define a novel metabolic rewiring, which can identify a new
therapeutic target(s...

## Key facts

- **NIH application ID:** 10248291
- **Project number:** 5F31CA243344-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Peter Kim
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,007
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248291

## Citation

> US National Institutes of Health, RePORTER application 10248291, Metabolism of Extracellular Matrix Supports Pancreatic Cancer Growth (5F31CA243344-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10248291. Licensed CC0.

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