Mazur, P.K. (Pawel K.)

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    Elevated NSD3 histone methylation activity drives squamous cell lung cancer
    (2021) Lu, X. (Xiaoyin); Jaremko, M. (Mariusz); Fang, B. (Bingliang); Roth, J.A. (Jack A.); Vicent, S. (Silvestre); Mazur, P.K. (Pawel K.); Hausmann, S. (Simone); Czaban, I. (Iwona); Yuan, G. (Gang); Flores, N.M. (Natasha M.); Sengupta, D. (Deepanwita); Gozani, O. (Or); Fischle, W. (Wolfgang); Jaremko, L. (Lukasz); Lofgren, S.M. (Shane M.); Azhibek, D. (Dulat); Kharchenko, V. (Vladlena); Wistuba, I.I. (Ignacio I.); Chua, K.F. (Katrin F.); Minna, J.D. (John D.); Angulo-Ibanez, M. (Maria); Shao, N.Y. (Ning-Yi)
    Amplification of chromosomal region 8p11-12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)(1-3). The FGFR1 gene is the main candidate driver of tumorigenesis within this region(4). However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful(5). Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11-12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.
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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.