Abstract 2358: miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis

Abstract

Abstract In colorectal cancer, the genetic mechanisms underlying the metastatic switch are still poorly understood. Here we show that overexpression of miRNA-483-3p, encoded by a frequently amplified gene locus encompassing also insulin-like growth factor 2, confers an aggressive phenotype to stem-like cells derived from colorectal cancer metastases (m-colospheres). As result of miRNA-483-3p ectopic overexpression, m-colospheres displayed (i) increased proliferative response to exogenous EGFR family ligands EGF and NRG1; (ii) increased spontaneous and growth factor-induced in vitro invasiveness and epithelial-mesenchymal transition (EMT); (iii) enhanced stem-cell frequency and resistance to differentiation. By transcriptomic analyses and functional validation, we found that miRNA-483-3p targets NDRG1, a known ‘metastasis suppressor', which is responsible for degradation of EGFR family members, in particular HER3. As result, ectopic or native miRNA-483-3p overexpression was associated with hyper-activation of the signaling pathway triggered by HER3, including AKT and GSK3β, responsible for activation of EMT transcription factors. Consistently, treatment of miRNA-483-3p overexpressing m-colospheres with HER3 specific antibodies counteracted their proliferative and invasive phenotype. The pro-invasive role of miRNA-483-3p in patients was further confirmed by (i) analysis of colorectal tumors, where miRNA-483-3p expression levels directly correlated with expression of EMT transcription factors and poor-prognosis, and (ii) downregulation of naturally occurring miRNA-483-3p overexpression, which prevented invasion of tumors formed by m-colosphere transplantation. These results indicate that miRNA-483-3p can support colorectal cancer invasion through a signaling pathway amenable to targeting in human patients. Citation Format: Ermes Candiello, Gigliola Reato, Federica Verginelli, Antonio D'Ambrosio, Gennaro Gambardella, Raffaella Albano, Paolo Luraghi, Paolo M. Comoglio, Andrea Bertotti, Livio Trusolino, Carla Boccaccio. miRNA-483-3p overexpression unleashes invasiveness of metastatic colorectal cancer by NDRG1 targeting and upregulation of the HER3-AKT axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2358.