# Role of PD2/Paf1 in Pancreatic Acinar to Ductal Metaplasia

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $421,180

## Abstract

Recent evidence has provided an understanding of the molecular mechanisms and genetic changes
underlying pancreatic ductal adenocarcinoma (PDAC) pathogenesis; however, limited information is available
on progression in the disease. Studies in several genetically engineered mouse models for PDAC suggest that
acinar cells, centroacinar cells, and/or postulated stem cells can be responsible for the development of
PDAC. This is believed to occur via a process termed “acinar-to-ductal metaplasia” (ADM), during which a
differentiated cell type (acinar) is reversibly replaced with another mature, differentiated cell type, a condition
also visible during inflammation, thereby underlining the predisposition of chronic pancreatitis patients to
PDAC. Pancreatic differentiation 2 (PD2), also known as polymerase associated factor-1 (Paf1), has been
found to be overexpressed in PDAC and to exhibit oncogenic potential. Our previous studies have further
defined the role of PD2/Paf1 in cell cycle regulation and in inducing chromatin structure remodeling in PDAC
cells. We have also demonstrated that PD2/Paf1 plays a major role in the multi-lineage differentiation of mouse
embryonic stem cells and maintains pancreatic cancer stem cells (PCSCs). Our preliminary efforts to
investigate the expression of PD2/Paf1 in KrasG12D;Pdx1Cre mouse model of PDAC showed that it is
differentially overexpressed in neoplastic pancreatic ducts during murine PDAC progression, as compared to
its strictly acinar expression in normal pancreas. PD2/Paf1 was specifically expressed in `intermediate
structures' expressing both acinar and ductal specific markers, representing `transitional cells' during
pancreatic acinar to ductal metaplasia. Further, we found that PD2/Paf1 is overexpressed along with PCSCs
markers in PDAC progression in mouse tissues and isolated CSCs. The multi-potent property of these CSCs
allows them to differentiate into several cell types. Therefore, the overall goal of this study is to define the role
of PD2/Paf1 in trans-differentiation of acinar cells to ductal cells during PDAC progression, through lineage-
differentiation of pancreatic CSC population. Based on these observations our central hypothesis is that
“PD2/Paf1 plays a significant role in the process of acinar-to-ductal metaplasia, thereby contributing to PDAC
progression, and its overexpression contributes to the ductal lineage-differentiation of pancreatic CSCs.” To
test this hypothesis, Aim 1 will focus on investigating the potential link of PD2/Paf1 in acinar-to-ductal
metaplasia using cerulein-induced mouse model of PDAC progression. Aim 2 will elucidate the mechanism(s)
of PD2/Paf1 in acinar-to-ductal metaplasia using acinar cells, organoid 3D-cultures, and PD2-/- animals. In Aim
3, we will understand the functional mechanism of PD2/Paf1 in ductal lineage-differentiation of pancreatic
CSCs in PDAC progression. Taken together, understanding of novel roles of PD2/Paf1 in ADM progression
through stem-lik...

## Key facts

- **NIH application ID:** 9857563
- **Project number:** 5R01CA210637-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Surinder K. Batra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,180
- **Award type:** 5
- **Project period:** 2017-03-06 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857563

## Citation

> US National Institutes of Health, RePORTER application 9857563, Role of PD2/Paf1 in Pancreatic Acinar to Ductal Metaplasia (5R01CA210637-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857563. Licensed CC0.

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