{"doi":"10.1038/s41392-024-01740-4","title":"Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma","abstract":"Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15a KO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.","journal":"Signal Transduction and Targeted Therapy","year":2024,"id":430334,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9508,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":588761,"name":"Marina Capece","orcid":"0000-0002-7624-8059","position":1,"is_corresponding":false},{"id":1233311,"name":"Luca Reggiani Bonetti","orcid":"0000-0002-9917-4080","position":2,"is_corresponding":false},{"id":378667,"name":"Giovanni Nigita","orcid":"0000-0001-8880-4334","position":3,"is_corresponding":false},{"id":379829,"name":"Federica Calore","orcid":null,"position":4,"is_corresponding":false},{"id":1049975,"name":"Sydney Rentsch","orcid":"0009-0003-4958-801X","position":5,"is_corresponding":false},{"id":1233312,"name":"Paolo Magistri","orcid":"0000-0001-8326-069X","position":6,"is_corresponding":false},{"id":1233700,"name":"Roberto Ballarin","orcid":null,"position":7,"is_corresponding":false},{"id":1018412,"name":"Fabrizio Di Benedetto","orcid":"0000-0002-6718-8760","position":8,"is_corresponding":false},{"id":634499,"name":"Rosario Distefano","orcid":"0000-0001-7241-7751","position":9,"is_corresponding":false},{"id":1233701,"name":"Roberto Cirombella","orcid":null,"position":10,"is_corresponding":false},{"id":774955,"name":"Andrea Vecchione","orcid":"0000-0002-5497-6856","position":11,"is_corresponding":false},{"id":1233313,"name":"Barbara Belletti","orcid":"0000-0003-2249-0285","position":12,"is_corresponding":false},{"id":1233314,"name":"Gustavo Baldassarre","orcid":"0000-0002-9750-8825","position":13,"is_corresponding":false},{"id":1007830,"name":"Francesca Lovat","orcid":null,"position":14,"is_corresponding":false},{"id":247626,"name":"Carlo M. Croce","orcid":"0000-0003-3788-1457","position":15,"is_corresponding":false},{"id":816500,"name":"Gian Luca Rampioni Vinciguerra","orcid":"0000-0003-0739-1668","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:59:16.092672Z","pmid":"38342897","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":[]}