Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer

Wan, Ledong, Lin, Kuan-Ting, Rahman, Mohammad Alinoor, Ishigami, Yuma, Wang, Zhikai, Jensen, Mads A, Wilkinson, John E, Park, Youngkyu, Tuveson, David A, Krainer, Adrian R (July 2023) Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer. Cancer Discovery, 13 (7). pp. 1678-1695. ISSN 2159-8274 (Public Dataset)

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Abstract

UNLABELLED: Inflammation is strongly associated with pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy. Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatitis and PDAC is not well understood. Here, we report that the splicing factor SRSF1 is highly expressed in pancreatitis, PDAC precursor lesions, and tumors. Increased SRSF1 is sufficient to induce pancreatitis and accelerate KRASG12D-mediated PDAC. Mechanistically, SRSF1 activates MAPK signaling-partly by upregulating interleukin 1 receptor type 1 (IL1R1) through alternative-splicing-regulated mRNA stability. Additionally, SRSF1 protein is destabilized through a negative feedback mechanism in phenotypically normal epithelial cells expressing KRASG12D in mouse pancreas and in pancreas organoids acutely expressing KRASG12D, buffering MAPK signaling and maintaining pancreas cell homeostasis. This negative feedback regulation of SRSF1 is overcome by hyperactive MYC, facilitating PDAC tumorigenesis. Our findings implicate SRSF1 in the etiology of pancreatitis and PDAC, and point to SRSF1-misregulated alternative splicing as a potential therapeutic target. SIGNIFICANCE: We describe the regulation of splicing factor SRSF1 expression in the context of pancreas cell identity, plasticity, and inflammation. SRSF1 protein downregulation is involved in a negative feedback cellular response to KRASG12D expression, contributing to pancreas cell homeostasis. Conversely, upregulated SRSF1 promotes pancreatitis and accelerates KRASG12D-mediated tumorigenesis through enhanced IL1 and MAPK signaling. This article is highlighted in the In This Issue feature, p. 1501.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > neoplasms
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing
organism description > animal
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
diseases & disorders > cancer > cancer types > pancreatic cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organism description > animal > mammal > rodent
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL labs > Tuveson lab
CSHL labs > Wigler lab
CSHL Cancer Center Program
CSHL Cancer Center Program > Cellular Communication in Cancer Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Histology Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL Cancer Center Shared Resources > Next Generation Sequencing Service
CSHL Cancer Center Shared Resources > Organoid Service
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 7 July 2023
Date Deposited: 21 Sep 2023 13:43
Last Modified: 24 Jun 2024 13:09
PMCID: PMC10330071
Related URLs:
Dataset ID:
  • PRJNA747810
URI: https://repository.cshl.edu/id/eprint/40933

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