# Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $353,419

## Abstract

Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue
 For the past thirty years, the survival rate for many cancers has improved, but survival for pancreatic
ductal adenocarcinoma (PDAC) has not, due to lack of both early detection methods and effective treatments.
Genetically modified mouse models have been widely used to study PDAC pathogenesis. However, mouse
cancer models may overlook some profound differences between human and mouse cells. To understand the
mechanisms of human PDAC tumorigenesis, we have established a novel system to isolate and genetically
manipulate primary acinar cells and ductal cells from normal human pancreatic tissue. This unique system
provides us with the opportunity to study the earliest changes in acinar or ductal cells during human PDAC
initiation. Pancreatitis-induced acinar to ductal metaplasia (ADM) is considered to be the earliest change during
PDAC development. Using our system, we recapitulated acinar to ductal metaplasia (ADM) in vitro at the
single-cell level, and identified that the TGFβ signaling pathway induces ADM in human acinar cells, partially
through SMAD4-mediated pathway. During ADM, cells gained new characteristic properties, including transient
proliferative capacity. However, the underlying mechanisms facilitating these changes remain unclear. We will
use our system to further investigate the ADM process. KRAS is the earliest and most frequently mutated
oncogene in pancreatic cancer. However, the mechanism by which oncogenic KRAS initiates neoplasia is not
well understood, and it is generally accepted that additional genetic/epigenetic alterations are required to
cooperate with KRAS mutation to initiate PDAC development. We found that mutant KRAS can extend the
proliferation of AD cells (acinar cells that have undergone ADM). We hypothesize that ADM-associated
changes cooperate with oncogenic KRAS to initiate pancreatic cancer. Although the SMAD4 pathway is
required for ADM, this gene is frequently mutated in the late-stage PDAC samples, suggesting that it may have
distinct functions under different cellular contexts. Interestingly, mouse PDAC models with SMAD4 deletion
developed intraductal papillary-mucinous neoplasm (IPMN) rather than pancreatic intraepithelial neoplasia
(PanIN). Whether this result is due to differences between mice and humans or due to the different cell
lineages from which the tumors developed remains to be discovered. The findings from the proposed
investigations will reveal human-specific aspects of PDAC tumorigenesis. The outcomes of these studies will
not only provide an opportunity to discover prognostic markers but also give us insight into PDAC
tumorigenesis that may lead to development of new methods for cancer treatment.

## Key facts

- **NIH application ID:** 10112846
- **Project number:** 5R01CA237159-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Pei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112846

## Citation

> US National Institutes of Health, RePORTER application 10112846, Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue (5R01CA237159-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112846. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*