Fragoso, R. (Rita)
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- The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas(American Society for Clinical Investigation, 2020) Lu, J. (Jun); Sun, T.Q. (Tian-Qiang); Román, M. (Marta); Miguéliz-Basterra, I. (Itziar); Vicent, S. (Silvestre); Entrialgo-Cadierno, R. (Rodrigo); Mazur, P.K. (Pawel K.); Hausmann, S. (Simone); Ponz-Sarvise, M. (Mariano); Erice, O. (Oihane); Chen, C.Z. (Chang-Zheng); Sweet-Cordero, E.A. (E. Alejandro); Flores, N.M. (Natasha M.); Tathireddy, A. (Anuradha); Sayles, L.C. (Leanne C.); Fragoso, R. (Rita); Guruceaga, E. (Elizabeth); Razquin, N. (Nerea); Valencia, K. (Karmele); Fortes, P. (Puri); Vallejo, A. (Adrian); Lecanda, F. (Fernando); Kostyrko, K. (Kaja); Lee, A.G. (Alex G.)Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found that the microRNA (miRNA) cluster including miR181ab1 is a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype, underscoring their nonredundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in 2 highly aggressive and difficult to treat KRAS-mutated cancers.