Wan, Ledong, Lin, Kuan-Ting, Rahman, Mohammad A, Wang, Zhikai, Park, Youngkyu, Tuveson, David A, Krainer, Adrian R (November 2021) Loss of compensatory feedback mechanism involving splicing factor SRSF1 accelerates Kras(G12D)-mediated pancreatic cancer initiation. In: AACR Virtual Special Conference on Pancreatic Cancer.
Abstract
KRAS is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), triggering the formation of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). However, the majority of pancreatic cells from KC (LSL-KrasG12D/+; Pdx-1-Cre) mice carrying the KrasG12D mutation remain morphologically normal for a long time, suggesting the existence of compensatory feedback mechanisms that buffer KrasG12D signaling, and that additional steps are required for disrupting cell homeostasis and promoting transformation. Here we found that splicing factor SRSF1, which is associated with cell transformation, is downregulated in the majority of morphologically normal pancreas cells with the KrasG12D mutation as a compensatory feedback mechanism. To assess the role of SRSF1 in PDAC, we generated a transgenic mouse strain (SC) with Dox-inducible pancreatic-specific expression of SRSF1 protein. Elevated SRSF1 alone is sufficient to induce pancreatitis and ADM transformation. By further crossing the SC strain with KrasG12D alone (KSC) or together with Trp53R172H (KPSC), we found that increasing SRSF1 accelerated KrasG12D-mediated tumor initiation and resulted in more aggressive PDAC. To address the underlying mechanisms of SRSF1’s involvement in the homeostatic response to KrasG12D mutation and in PDAC initiation, we generated organoid lines from the above mouse strains. Following Dox induction, elevated SRSF1 with Kras WT or KrasG12D consistently activated MAPK signaling, which is one of the top negatively enriched pathways in response to KrasG12D. Furthermore, SRSF1 promoted the expression of Il1r1—an IL1 receptor associated with the activation of MAPK signaling—by regulating an alternative-splicing event in the 5’UTR to generate a more stable mRNA isoform. We conclude that decreased SRSF1 is a compensatory feedback mechanism in pancreatic cells against the KrasG12D mutation, whose disruption facilitates PDAC initiation.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Fearon lab CSHL labs > Krainer lab CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | November 2021 |
| Date Deposited: | 06 Dec 2021 19:24 |
| Last Modified: | 06 Dec 2021 19:24 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40442 |
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