Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma

作     者：Gian Luca Rampioni Vinciguerra Marina Capece Luca Reggiani Bonetti Giovanni Nigita Federica Calore Sydney Rentsch Paolo Magistri Roberto Ballarin Fabrizio Di Benedetto Rosario Distefano Roberto Cirombella Andrea Vecchione Barbara Belletti Gustavo Baldassarre Francesca Lovat Carlo M.Croce Gian Luca Rampioni Vinciguerra;Marina Capece;Luca Reggiani Bonetti;Giovanni Nigita;Federica Calore;Sydney Rentsch;Paolo Magistri;Roberto Ballarin;Fabrizio Di Benedetto;Rosario Distefano;Roberto Cirombella;Andrea Vecchione;Barbara Belletti;Gustavo Baldassarre;Francesca Lovat;Carlo M.Croce

作者机构：Department of Cancer Biology and Genetics and Comprehensive Cancer CenterThe Ohio State UniversityColumbus 43210 OHUSA Department of Clinical and Molecular MedicineFaculty of Medicine and PsychologySant’Andrea HospitalUniversity of Rome“Sapienza”Rome 00189Italy Department of DiagnosticClinic and Public Health MedicineUniversity of Modena and Reggio EmiliaModena 41100Italy Hepato-pancreato-biliary Surgery and Liver Transplantation UnitUniversity of Modena and Reggio EmiliaModena 41100Italy Division of Molecular OncologyCentro di Riferimento Oncologico di Aviano(CRO)Istituto di Ricovero e Cura a Carattere Scientifico(IRCCS)National Cancer InstituteAviano 33081Italy 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2024年第9卷第3期

页      面：1132-1146页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：We thank the Genomic Shared Resource at The Ohio State University Comprehensive cancer Center(OSU CCC),supported by the Cancer Center Support Grant P30CA016058,for conducting the Affymetrix microarray assays,in particular Dr.Paolo Fadda We acknowledge resources from the Campus Microscopy and Imaging Facility(CMIF)at The Ohio State University,in particular Dr.Jeffrey R.Tonniges for his valuable support This facility is supported in part by grant P30 CA016058,National Cancer Institute,Bethesda,MD Histology and immunohistochemistry services were provided by the Comparative Pathology&Digital Imaging Shared Resource,Department of Veterinary Biosciences and the Comprehensive Cancer Center,The Ohio State University,Columbus,OH.Figs.4a,6g and Supplementary Fig.10a of this manuscript were realized by using the software BioRender.com supported by NIH/NCI grant R35 CA197706 to C.M.C.G.B.was funded by Ricerca Corrente of Ministero della Salute 

主　　题：IGF1R Fra miR 

摘      要：Pancreatic ductal adenocarcinoma(PDAC)is a lethal disease,characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient *** aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor *** of the onco-suppressor miR-15a has been extensively documented in ***,we identified the transcription factor Fos-related antigen-2(Fra-2)as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient *** 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 ***,we discovered that miR-15a repressed IGF1R expression via Fra-2 *** miR-15a-low context,IGF1R hyperactivated mTOR,modulated the autophagic flux and sustained PDAC growth in nutrient *** a genetic mouse model,Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet ***,nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent ***,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.