Journal Article

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

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

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1504 / Adenocarcinoma / Animals / Blood vessels / Cancer Research / Carcinoma, Pancreatic Ductal - pathology / Cell Biology / Cell Line, Tumor / Cellular stress response / Fos-related antigen / Fos-Related Antigen-2 / Humans / Insulin-like growth factor I / Internal Medicine / Medicine / Medicine & Public Health / Mice / MicroRNAs - genetics / MicroRNAs - metabolism / Oncology / Pancreatic cancer / Pancreatic Neoplasms - pathology / Pathology / Receptor, IGF Type 1 - genetics / Signal transduction / TOR protein / TOR Serine-Threonine Kinases / Tumor Microenvironment / Tumors