# Project 2: Splicing Dysregulation in Cancer

> **NIH NIH P01** · COLD SPRING HARBOR LABORATORY · 2024 · $641,584

## Abstract

PROJECT 2 – RNA-SPLICING DYSREGULATION IN CANCER
PROJECT SUMMARY
The overarching goal of Project 2 is to understand the various roles of alternative splicing in pancreatic and
breast cancer, and to exploit cancer-specific features of this process to develop targeted-therapeutic
approaches. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset
of the isoforms that are inappropriately expressed contribute to tumorigenesis or altered cell metabolism. The
mechanisms and pathways through which the splicing-factor oncoprotein SRSF1 accelerates transformation of
pancreas ductal cells, and its reciprocal regulation with mutant KRAS, will be investigated. The spliceosomal
core component BCAS2 will be studied to understand the impact of its elevated expression on alternative splicing
and tumorigenesis in pancreatic and breast cancers. Organoid models, as well as orthotopic and genetic mouse
models, will be used to study tumorigenesis promoted by these splicing factors when their expression is elevated
in pancreatic or breast cancer, with an emphasis on basal-like subtypes. High-throughput RNA-sequencing and
computational analyses will be employed to identify and compare the affected splicing targets of SRSF1 and
BCAS2 in these different cancer contexts, and selected target isoforms will be characterized and manipulated to
evaluate their contributions to tumorigenesis and potential as therapeutic targets. One key event, alternative
splicing of pyruvate kinase M pre-mRNA, which controls the distinctive glycolytic metabolism of cancer cells, will
be thoroughly investigated as a potential therapeutic target, by specifically manipulating this process in vitro and
in vivo, using antisense technology and organoid and mouse models of pancreatic and breast cancer.

## Key facts

- **NIH application ID:** 10773001
- **Project number:** 5P01CA013106-52
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Adrian R Krainer
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $641,584
- **Award type:** 5
- **Project period:** 1997-02-10 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773001

## Citation

> US National Institutes of Health, RePORTER application 10773001, Project 2: Splicing Dysregulation in Cancer (5P01CA013106-52). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10773001. Licensed CC0.

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