{"doi":"10.1101/2021.10.13.464210","title":"Loss of KRAS <sup>G12D</sup> feedback regulation involving splicing factor SRSF1 accelerates pancreatic cancer","abstract":"Abstract The gene encoding KRAS GTPase is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), triggering the formation of precursor lesions, i.e., acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). However, the majority of pancreatic cells from KC ( LSL-Kras G12D/+ ; Pdx-1-Cre ) mice expressing the Kras G12D mutation remain morphologically normal for a long time, suggesting the existence of compensatory feedback mechanisms that buffer aberrant Kras G12D signaling, and that additional steps are required for disrupting cell homeostasis and promoting transformation. Here we report a feedback mechanism in which the ubiquitously expressed splicing factor SRSF1—which is associated with cell transformation in multiple cell types—is downregulated in the majority of morphologically normal pancreas cells with the Kras G12D mutation. Conversely, increasing SRSF1 expression disrupts cell homeostasis by activating MAPK signaling, in part by regulating alternative splicing and mRNA stability of interleukin 1 receptor type 1 ( Il1r1 ). This disruption in homeostasis in turn accelerates Kras G12D -mediated PDAC initiation and progression. Our results demonstrate the involvement of SRSF1 in the pancreatic-cell homeostatic response against the Kras G12D mutation, dysregulation of which facilitates PDAC initiation. One-Sentence Summary Splicing factor SRSF1 is involved in KRAS G12D feedback regulation and pancreatic-cancer tumorigenesis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":227165,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":676672,"name":"Kuan‐Ting Lin","orcid":"0000-0003-1294-1142","position":1,"is_corresponding":false},{"id":676674,"name":"Mohammad Alinoor Rahman","orcid":"0000-0003-1553-8316","position":2,"is_corresponding":false},{"id":554178,"name":"Zhikai Wang","orcid":"0000-0002-8565-6011","position":3,"is_corresponding":false},{"id":456036,"name":"Mads A. Jensen","orcid":null,"position":4,"is_corresponding":false},{"id":266280,"name":"Youngkyu Park","orcid":"0000-0003-1169-6739","position":5,"is_corresponding":false},{"id":103976,"name":"David A. Tuveson","orcid":"0000-0002-8017-2712","position":6,"is_corresponding":false},{"id":576318,"name":"Adrian R. Krainer","orcid":"0000-0001-9024-9501","position":7,"is_corresponding":false},{"id":830976,"name":"Ledong Wan","orcid":"0000-0002-2450-3986","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:42.179886Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}