# Role of nonsense mediated RNA decay in pancreatic cancer

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $403,427

## Abstract

Nonsense mediated RNA decay (NMD) is a mechanism to rapidly degrade select mRNAs. Recent studies
have found that the UPF1 gene, required for NMD, is strikingly mutated and inactivated in >80% of
adenosquamous pancreatic cancer (ASPC), a particularly aggressive form of pancreatic cancer. We have
determined that UPF1 mutations in pancreatic cancer result in decreased UPF1 expression. Other mutations
recently reported to inactivate NMD are found in pancreatic ductal adenocarcinoma, and we have reported that
many of the stresses commonly found in pancreatic cancer repress NMD activity. NMD inhibition promotes the
growth of transformed cells in soft agar, subcutaneous explants, and in an orthotopic pancreatic transplant
model. Our overall goal is to better understand how NMD inhibition augments tumor growth and explore how
we can exploit NMD inhibition for therapeutic gain in pancreatic cancer.
RNA stability screens, RNAseq, and metabolomics screens have identified Notch signaling and Glycolysis as
NMD regulated pathways. Both Notch signaling and Glycolysis play an important role in pancreatic cancer in
general, and recent pancreatic cancer molecular classification studies indicate that these two pathways are
particularly active in ASPC, where NMD is typically genetically inactivated. Importantly these pathways can
also be targeted. In Aim 1 we will identify the mechanism and significance of NMD inhibition on Notch
activation in pancreatic cancer. Based on our preliminary data we hypothesize that reduced NMD inhibition
expression stabilizes Notch ligands and receptors, and the activation of Notch signaling represses e-cadherin
expression to play a key role in metastases and chemo-resistance. However we also hypothesize that NMD
inhibited pancreatic cancers will be particularly susceptible to Notch inhibitors. In Aim 2 we will determine how
reduced NMD inhibition regulates metabolic pathways and exploit this for therapeutic gain. Based on our
preliminary data, we hypothesize that NMD inhibition stabilizes alternatively spliced transcripts encoding
members of the mitochondrial respiration system, and this activates glycolysis and the pentose phosphate
shunt. The activation of these pathways should render tumors with UPF1 mutations more sensitive to clinically
available mitochondrial inhibitors and other metabolic inhibitors, as indicated by preliminary focused shRNA
synthetic lethality screens. For both Aims we will use a variety of in vitro cell biology, biochemical, and
molecular techniques. We will validate our in vitro findings with unique ASPC tissue arrays, as well as a novel
genetically engineered mouse in which we can temporally down-regulate UPF1 expression in pancreas, and
can thus faithfully model the consequences of UPF1 mutations found in ASPC.

## Key facts

- **NIH application ID:** 9948587
- **Project number:** 5R01CA211687-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MARK Reid PHILIPS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,427
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948587

## Citation

> US National Institutes of Health, RePORTER application 9948587, Role of nonsense mediated RNA decay in pancreatic cancer (5R01CA211687-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948587. Licensed CC0.

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