# Stromal and vascular inputs into pancreatic cancer tumor neighborhoods

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $624,279

## Abstract

PROJECT SUMMARY
Cancer cells are the organizers of their surroundings and create a tumor microenvironment (TME) favoring cell
division even when oxygen and nutrients are limiting. An extreme example is pancreatic ductal adenocarcinoma
(PDAC) which establishes a metabolically hostile ecosystem characterized by a hypo-vascular, severely hypoxic,
and nutrient deprived stroma. Clinical trials targeting components of the PDAC stroma have not improved overall
survival in unselected cohorts. Thus, while opportunities for targeting the PDAC TME exist, the development of
anti-stromal therapies will require a better understanding of inter- and intra-tumoral heterogeneity.
Our labs have studied two features of the PDAC stroma: the vasculature and CAFs. By analyzing multiple human
datasets, and mouse models, we found that a significant portion of human PDACs (~10%) are hyper-vascular.
In murine models, hyper-vascularity is associated with increased sensitivity to angiogenesis inhibitors. In
addition, our preliminary studies have shown that in the more typical hypo-vascular tumors, hypoxia renders
PDAC tumor cells incapable of synthesizing unsaturated fatty acids (uFAs), and therefore critically dependent
upon lipids supplied by neighboring CAFs for their survival. Based on these data, we hypothesize that cancer-
associated micro-vasculature and lipid secreting fibroblasts represent under-exploited, clinically relevant targets
within the PDAC stroma.
Here, we propose an innovative approach to delineate the cellular mechanisms by which tumor cells build and
maintain critical metabolic “supply chains” and how regional differences within tumors influence nutrient
utilization and vascular intravasation. Our proposal addresses both basic and translational questions and utilizes
human tissue resources, implantable and genetically engineered mouse models, platforms to assess stromal
geography and metabolic features, and cancer-on-chip techniques for ex vivo modeling. Our ultimate goal is to
understand and manipulate the major sources from which PDAC cells derive essential nutrients (especially vital
uFAs) – focusing on micro-vessels and fibroblasts.
Aim 1. Determine the causes and consequences of vascular heterogeneity in PDAC
Aim 2. Delineate molecular mechanisms and therapeutic opportunities underlying stromal support of
lipid metabolism in PDAC

## Key facts

- **NIH application ID:** 10886118
- **Project number:** 5R01CA276512-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** M. CELESTE SIMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $624,279
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886118

## Citation

> US National Institutes of Health, RePORTER application 10886118, Stromal and vascular inputs into pancreatic cancer tumor neighborhoods (5R01CA276512-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886118. Licensed CC0.

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