# Defining and Targeting Malic Enzyme Dependence in Pancreatic Cancer

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $69,802

## Abstract

Project Summary/Abstract
Pancreatic adenocarcinoma (PDA) is the most lethal major cancer, with a 5-year survival rate
below 10%. This is largely due to the lack of effective treatment options. The physiology and
biochemical nature of pancreatic tumors is fundamental to this therapeutic resistance. PDA cells
exist in a dense, fibrotic and thus, nutrient-depleted tumor microenvironment. Predictably,
metabolism is reprogrammed in PDA cells to fuel their maintenance and growth. For example,
our group recently described a non-canonical pathway utilized by PDA cells to mediate oxidative
stress, thereby permitting their full growth potential. More recently, my preliminary results
revealed that inhibition of malic enzyme 1 (ME1), the last enzyme in this metabolic pathway, can
significantly blunt tumor growth in vitro and in vivo. There are three ME isoforms in mammals,
ME1-3. I identified an inverse correlation between ME1 dependence and ME2 expression in
PDA cells. In other words, ME1 dependent PDA cells have low/no ME2, and ME2 expressing
PDA cells are resistant to ME1 inhibition. Intriguingly, nearly 50% of PDA express low/no ME2.
ME2 is in close chromosomal proximity to SMAD4, a tumor suppressor lost in PDA. Based on
their genomic location, co-loss of ME2 also frequently occurs. Therefore, the loss of ME2
provides a potential context for ME1-dependent synthetic lethality and a patient stratification
method for ME1 inhibitors. There is therefore a fundamental need to understand the functional
roles of MEs in order to exploit this unique therapeutic vulnerability in PDA.
The working hypothesis of this project is that functional redundancy exists between cytosolic
ME1 and mitochondrial ME2. When ME1 is impaired, ME2 provides metabolic/redox
compensatory activity. Further, loss of ME2 expression provides a context for ME1-dependent
synthetic lethality. This will be tested in two parts. (Aim 1) Mechanistically, the metabolic and
subcellular functions of MEs in PDA growth will be defined. The metabolic roles of MEs will be
examined by steady-state metabolomics, isotope tracing and flow cytometry following alteration
of ME expression. The subcellular localization and potential physical interactions of MEs will
also be investigated. (Aim 2) Functionally, the compensatory effect between ME1 and ME2 on
PDA growth will be examined in vitro, ex vivo and in vivo using genetic knockdown/out and
overexpression. These studies will contribute to our understanding of the mechanisms that
regulate metabolism in PDA and the roles of MEs. Further they will pave the way for the
development of ME1-targeted drugs for PDA, while also providing a strategy for patient
stratification.

## Key facts

- **NIH application ID:** 10394789
- **Project number:** 5F32CA247492-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Mengrou Shan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,802
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394789

## Citation

> US National Institutes of Health, RePORTER application 10394789, Defining and Targeting Malic Enzyme Dependence in Pancreatic Cancer (5F32CA247492-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10394789. Licensed CC0.

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