# Networks for functional regulation of pancreatic acinar-ductal metaplasia and epithelial plasticity

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $491,862

## Abstract

PROJECT SUMMARY
Acinar epithelial cells can undergo a highly regulated acinar-to-ductal metaplasia (ADM), wherein
resident acinar cells of the pancreas undergo trans-differentiation into ductal-like cells. In the
context of damage to pancreas (pancreatitis), this process is adaptive and apparently reversible,
where the ductal-like cells that have undergone ADM completely restore their acinar identity by
undergoing acinar cell reprogramming. However, in the presence of mutant Kras, ADM cells
remain ductal and are unable to reprogram into acinar cells, forcing their continued development
down the ductal lineage. We have identified central molecular determinants of ADM, including
key transcription factors such Prrx1 and Sox9. Despite this, very little remains known regarding
the alterations that distinguish “adaptive” ADM (i.e. pancreatitis or injury-induced), which does
not result in PanIN (preneoplasia), from “oncogenic” ADM (i.e. mutant Kras induced), which does.
Additional features of ADM process are unknown – namely, what ‘gatekeepers’ control trans-
differentiation of acinar cells and how the pancreas microenvironment participates in these cell
fate transitions.
Our objective is to study acinar cell fate and to define the key points at which the tightly regulated
process of ADM is dysregulated. First, in several prior studies, we have defined Prrx1 as a central
determinant of ADM formation. Second, we have begun to identify differences in the chromatin
landscape of adaptive versus oncogenic ADM and highlight the AP-1 member Fra1 as a firm
mediator distinguishing oncogenic and adaptive ADM through new in vivo data. Third, we have
identified new cell extrinsic roles for epithelial Fra1 to act as an organizer of a microenvironment
that fosters ADM. Together, our central hypothesis is that oncogenic ADM features central
mediators distinct from those in adaptive ADM that drive subsequent inflammatory and
preneoplastic states. Our collaborative teams (Rustgi-Columbia, NYC and Chandwani-Weill
Cornell, NYC) will pursue the following interrelated Specific Aims: (1) Define the role of Fra-1
(cell intrinsic) in mediating the switch from adaptive to oncogenic ADM; (2) Delineate how
coordinate activation of Prrx1 and Sox9 controls acinar cell responses in ADM; (3)
Determine the cell-extrinsic effect(s) of Fra-1 in organizing an ADM-promoting
microenvironment. Together, our innovative studies now focus on three specific aspects of the
ADM process – Prrx1-Sox9 activation, Fra1 dependency, and microenvironment contributions --
–– that will further illuminate the key biological processes that ensure an appropriate response to
tissue-level injury in the pancreas.

## Key facts

- **NIH application ID:** 10446561
- **Project number:** 2R01DK060694-20A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Anil K Rustgi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $491,862
- **Award type:** 2
- **Project period:** 2002-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446561

## Citation

> US National Institutes of Health, RePORTER application 10446561, Networks for functional regulation of pancreatic acinar-ductal metaplasia and epithelial plasticity (2R01DK060694-20A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10446561. Licensed CC0.

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