# The transcriptional and epigenetic landscape of cell fate changes in murine pancreatic cancer initiation and metastasis

> **NIH NIH F31** · JOHNS HOPKINS UNIVERSITY · 2021 · $46,036

## Abstract

Project Summary
 Pancreatic cancer, the fourth most lethal cancer in the United States and rising, represents
3% of all cancer cases diagnosed per year but a disproportionate 8% of all cancer deaths per
year. Because of a lack of early symptoms, pancreatic cancer tends to be diagnosed in later
stages, often post-metastasis: fewer than 20% of patients are candidates for surgical resection.
This contributes to a dismally low average 5-year survival rate of 9% across all stages at
diagnosis; thus, higher resolution methods for early detection and abrogation are crucial.
 Pancreatic ductal adenocarcinoma (PDAC), a cancer of the exocrine cells of the
pancreas, represents 93% of pancreatic cancer cases diagnosed per year. The initiation of
PDAC is preceded by a characteristic cell fate change called acinar-to-ductal metaplasia (ADM).
ADM is a naturally occurring, reversible process during pancreatic injury or inflammation.
However, upon an oncogenic G12D mutation of the KRAS gene, a post-ADM state cannot be
reversed, facilitating progression to a PDAC precursor state. ADM is mediated by changes in
transcriptional and epigenetic regulation. In particular, the pluripotency factor Klf4 has been
implicated as a master regulator of ADM.
 Epigenetic reprogramming has also been revealed as a major driver of PDAC
progression and metastasis. A recent study found genome-wide Foxa1-mediated enhancer
reprogramming to be a major driver of PDAC metastasis. Foxa1 and 2 are pioneer factors are
known also to be necessary for pancreatic development. Furthermore, genome-scale
reprogramming of histone modifications has also been demonstrated to drive the transition from
local to distant metastasis. The role of cell fate-associated factors such as Klf4 and Foxa1 in
cancer-associated transformations urges investigation of the relationship between pancreatic
cell fate plasticity, reprogramming, and oncogenesis.
 Cell fate-related changes in the transcriptome and epigenome during ADM and PDAC
metastasis have not been comprehensively profiled. The proposed project takes advantage of
murine models of ADM, PDAC, and metastasis to characterize this relationship between
changes in cell identity and oncogenesis. We aim to 1) determine how the transcriptome and
epigenome change during ADM, and 2) determine the parallels in epigenetic dysregulation
between PDAC progression and ADM. We hope that completion of this project will reveal novel
properties of PDAC for potential early detection and therapeutic targeting.

## Key facts

- **NIH application ID:** 10145988
- **Project number:** 1F31CA250489-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Emily Lo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145988

## Citation

> US National Institutes of Health, RePORTER application 10145988, The transcriptional and epigenetic landscape of cell fate changes in murine pancreatic cancer initiation and metastasis (1F31CA250489-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145988. Licensed CC0.

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