# TBEL Project 2

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $282,471

## Abstract

PROJECT 2 – ABSTRACT
The estimated prevalence of pancreatic cystic neoplasms (PCNs) is between 20–30% with intraductal papillary
mucinous neoplasm (IPMNs) accounting for half of them. Depending on the morphology, location, and genetics
IPMNs can be of high-risk developing pancreatic ductal adenocarcinoma (PDAC) and as such significantly
diminishing patient’s survival. While RNF43 is only mutated in a small fraction of PDAC, RNF43 mutations are
prevalent in a high frequency in IPMNs. Although RNF43 has been identified as a negative regulator of Wnt
signaling in colorectal cancers and other preclinical models including PDAC, a phase 1 clinical trial of a Wnt
inhibitor in patients with RNF43 mutated solid cancers (including PDAC) has been proven disappointing. Other
likely organ specific functions of RNF43 might be of great advantage for IPMN progression. Utilizing a conditional
knockout mouse model of RNF43 in context of Kras mutation we found that RNF43 abrogates the mitochondrial
properties and functions while loss of RNF43 improved mitochondrial quality control, increased unfolded protein
response (UPR) and ER stress. These findings let us hypothesize that loss of RNF43 may deregulate the
crosstalk of these organelles in order to maintain proteostasis, metabolic control, and cell survival.
Employing an autochthonous mouse model for functional loss of RNF43 in the context of Kras (generated in the
Dr. Maitra lab), primary genetically engineered cell lines (generated in the Dr. Lyssiotis lab) and human IPMN
derived organoids (generated in the Dr. Wood lab; see Project 3) we propose to pursue the following aims:
First we will investigate whether RNF43 regulates mitochondrial dynamics including biogenesis, fission, fusion
and mitophagy to inhibit IPMN pathogenesis (Aim 1). Further, we will investigate whether RNF43 blocks IPMN
pathogenesis by limiting ER stress through management of ER-mitochondrial dynamics (Aim 2). Lastly, we will
determine whether loss of RNF43 creates a synthetic essentiality for sustained OXPHOS (Aim 1) and
whether/how OXPHOS inhibition impacts the multistep progression in an autochthonous KRC model of
pancreatic cystic neoplasia (Aim 3). Overall, these studies will elucidate the functional role of RNF43 in
mitochondria quality control, ER-mitochondrial dynamics and how this impacts IPMN pathogenesis and
progression.

## Key facts

- **NIH application ID:** 10922844
- **Project number:** 5U54CA274371-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** ANIRBAN MAITRA
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $282,471
- **Award type:** 5
- **Project period:** 2022-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10922844

## Citation

> US National Institutes of Health, RePORTER application 10922844, TBEL Project 2 (5U54CA274371-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10922844. Licensed CC0.

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