# RBFOX2 deregulation promotes pancreatic cancer progression through alternative splicing

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2023 · $469,135

## Abstract

SUMMARY
Splicing is a critical biological process in cancer initiation and progression. In pancreatic cancer, few studies
have investigated the role of splicing regulators or their spliced targets in disease progression. Using a high-
throughput, genome-wide genetic screen in vivo for novel events promoting KRAS-driven pancreatic ductal
adenocarcinoma (PDAC), we recently identified a unique role for the RNA splicing factor RBFOX2 as a latent
tumor suppressor driving disease progression. We showed RBFOX2 nuclear abundance is significantly
decreased in poorly differentiated human PDAC and that RBFOX2 depletion promotes a highly metastatic
disease in orthotopic models. We found RBFOX2 loss promotes exon skipping events associated with stem cell
potential and invasion, including ABI1. We hypothesize that RBFOX2-mediated splice-switching in key regulators
of cell invasion and differentiation programs is central to its role in promoting PDAC progression. In this proposal,
we will examine the oncogenic role of these RBFOX2-mediated splicing events in PDAC progression. In Aim 1,
we will investigate the oncogenic role(s) of the ABI1∆Ex9 isoform alternatively spliced by RBFOX2 using
proteomics approaches to elucidate novel protein interactions and secondary modifications contributing to
ABI1∆Ex9 function in driving invasive phenotypes. In Aim 2, we will investigate the contribution of “ESC-like”
exon exclusion events regulated by RBFOX2 to PDAC cell differentiation and disease progression using i) splice-
switching Anti-Sense Oligonucleotides (AONs) to mimic exon-skipped isoforms and investigate their
cooperativity in driving ex vivo stem cell-like phenotypes and ii) inducible cDNA isoforms to understand their role
in promoting disease progression in vivo. In Aim 3, we will develop an RBFOX2 splicing signature using PDXs
and PDOs from patients with rapid relapse and progression-free disease using state of the art splicing analysis
platforms (bulk and scRNAseq PacBio/isoseq coupled to Illumina short read sequencing) and investigate its
association with disease relapse. We expect that our study will reveal the biological relevance of the RBFOX2-
promoted oncogenic splicing program in pancreatic cancer progression and identify new molecular vulnerabilities
that can be harnessed to improve disease outcomes for pancreatic cancer patients.

## Key facts

- **NIH application ID:** 10638347
- **Project number:** 1R01CA279713-01
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Karen M Mann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $469,135
- **Award type:** 1
- **Project period:** 2023-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10638347

## Citation

> US National Institutes of Health, RePORTER application 10638347, RBFOX2 deregulation promotes pancreatic cancer progression through alternative splicing (1R01CA279713-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10638347. Licensed CC0.

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