# Metabolic regulation of pancreatic metaplasia and neoplasia

> **NIH NIH K99** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $125,000

## Abstract

PROJECT SUMMARY
Acinar-to-ductal metaplasia (ADM) is a regenerative state that leads to repair of the pancreas
after injury. During ADM, acinar cells transdifferentiate to a duct-like cell and become
proliferative. ADM is typically reversible; however, ADM is also a risk factor for the development
of pancreatic ductal adenocarcinoma. Activating mutations in KRAS lead to persistent ADM and
progression to pancreatic intraepithelial neoplasia (PanIN) and cancer. Many studies describe
how cell metabolism is reprogrammed in cancer, though little is known about the role of
metabolism in regulating precancerous stages, like ADM and PanIN. I hypothesize that 1. cell
metabolism is altered in ADM to upregulate redox homeostasis, and 2. healthy acinar cells
maintain a metabolic microenvironment that is restrictive for ADM and PanIN progression.
Previous work shows that genes for NADPH-producing enzymes, Glucose-6-phosphate
dehydrogenase (G6pd) and Malic enzyme 1 (Me1) are upregulated during ADM to maintain
redox homeostasis and glutathione recycling. Preliminary also suggest that glutathione
biosynthesis pathways are necessary for controlled ADM development. Aim 1 will
mechanistically focus on Me1 and determine how Me1-loss contributes to ADM and PanIN
formation. The experiments proposed in Aim 1 use genetically engineered mouse models of
pancreatic cancer, steady-state metabolomics, isotope tracing, and ex vivo primary acinar cell
culture. Aim 2 will address if altered glutathione biosynthesis promotes ADM formation. It will
interrogate if blocking cystine import (via loss of a subunit of the system xC– antiporter) and a
rate-limiting enzyme in glutathione synthesis increases reactive oxygen species in the cell and
promotes ADM. Aim 3 (R00 focus) will determine if healthy acinar cells contribute to a restrictive
environment for the development of ADM and PanIN, even when oncogenic Kras is present.
Preliminary experiments suggest that healthy acinar cells secrete metabolites to inhibit adjacent
cells from undergoing ADM. Pilot spatial transcriptomic experiments have also identified
potential metabolic genes important for ADM restriction. This aim uses inducible mouse models
of Kras-driven pancreatic cancer, metabolomics, and spatial transcriptomics. Together, the aims
presented in this proposal will provide new mechanistic insights on how metabolic pathways
control the formation of precancerous states in the pancreas.

## Key facts

- **NIH application ID:** 10985624
- **Project number:** 1K99GM159354-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Megan DeAnna Radyk
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,000
- **Award type:** 1
- **Project period:** 2024-09-06 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985624

## Citation

> US National Institutes of Health, RePORTER application 10985624, Metabolic regulation of pancreatic metaplasia and neoplasia (1K99GM159354-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10985624. Licensed CC0.

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