# Mechanisms of Pancreatic Inflammation, Tissue Repair and Carcinogenesis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $342,097

## Abstract

Abstract – Mechanisms of pancreatic inflammation, tissue repair and carcinogenesis.
The
 Pancreatic ductal adenocarcinoma, or pancreatic cancer, is one of the deadliest human
malignancies, and little progress has been achieved in its treatment. Pancreatic cancer is characterized
by an extensive fibrotic stroma, which includes vascular elements, infiltrating immune cells, extracellular
matrix and a large number of fibroblasts responsible for creating a fibrotic microenvironment. The
fibroblast population is presumed to derive from pancreatic stellate cells, although this notion has never
been confirmed through lineage tracing studies due to the lack of appropriate tools. The role of the
fibroblasts within the stroma is similarly controversial, with different studies ascribing a pro-tumor or anti-
tumor function to these cells. Understanding the nature and biological role of pancreatic fibroblasts is
necessary to set the stage for therapeutic strategies targeting the stroma as well as tumor cells.
 Although typically studied/treated as homogenous, the fibroblasts within the pancreatic stroma
are a heterogeneous population, with potentially distinct functional properties. We have identified a
sub-population of perivascular fibroblasts that are present within the normal pancreas and express the
transcription factor Gli1, an effector and target gene of the Hedgehog signaling pathway. Moreover, we
have identified a population of cells within the pancreas with mesenchymal stem cell (MSC) properties.
Preliminary data indicate that these two populations might, completely or in part, overlap, and that they
regulate the immune infiltration and polarization. The goal of this proposal is to functionally characterize
the Gli1+ fibroblast population in pancreatic cancer. We will pursue this goal through 3 Specific Aims.
In Aim 1, we will first lineage-trace perivascular Gli1+ fibroblasts in the normal pancreas to determine
whether they contribute to the fibrotic reaction during carcinogenesis. Second, we will ablate this cell
population at different stages of tumor development to determine whether they promote, or rather inhibit,
tumor growth. In Aim 2, we will investigate the overlap between the MSC population and Gli1+
fibroblasts within the fibrotic pancreas, and study their ability to regulate immune function. Finally, in Aim
3, we will complement the other Aims by investigating the nature and role of Gli1 expressing immune
cells. Throughout the Aims, we will determine whether the effects mediated by Gli1+ cells can be
recapitulated by inhibition of Hedgehog signaling. These Aims will vertically enhance our understanding
of the origin and function of the pancreatic cancer stroma, and might provide insight into the recent
failure of clinical trials against the stroma, such as Hedgehog inhibition. The long-term goal of this
application is to identify new cellular components that might be targeted therapeutically to benefit
pancreatic cancer patients.
Througho...

## Key facts

- **NIH application ID:** 9970207
- **Project number:** 5R01CA151588-10
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Marina Pasca Di Magliano
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,097
- **Award type:** 5
- **Project period:** 2010-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970207

## Citation

> US National Institutes of Health, RePORTER application 9970207, Mechanisms of Pancreatic Inflammation, Tissue Repair and Carcinogenesis (5R01CA151588-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970207. Licensed CC0.

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