Consequences of Zmat3 loss in c-MYC- and mutant KRAS-driven tumorigenesis
TP53 is a critical tumor suppressor that is mutated in approximately 50% of human cancers. Unveiling the downstream target genes of TP53 that fulfill its tumor suppressor function is an area of intense investigation. Zmat3 (also known as Wig-1 or PAG608) is one such downstream target of p53, whose loss in hemopoietic stem cells lacking the apoptosis and cell cycle regulators, Puma and p21, respectively, promotes the development of leukemia. The function of Zmat3 in tumorigenesis however remains unclear. Here, to investigate which oncogenic drivers co-operate with Zmat3 loss to promote neoplastic transformation, we utilized Zmat3 knockout mice in models of c-MYC-driven lymphomagenesis and KrasG12D-driven lung adenocarcinoma development. Interestingly, unlike loss of p53, Zmat3 germline loss had little impact on the rate of tumor development or severity of malignant disease upon either the c-MYC or KrasG12D oncogenic activation. Furthermore, loss of Zmat3 failed to rescue KrasG12D primary lung tumor cells from oncogene-induced senescence. Taken together, we conclude that in the context of c-MYC-driven lymphomagenesis or mutant KrasG12D-driven lung adenocarcinoma development, additional co-occurring mutations are required to resolve Zmat3 tumor suppressive activity. ; This work was supported by the Australian Phenomics Network (APN); the Australian National Health and Medical Research Council (NHMRC) Project Grant to M.J.H. (1145728), to M.J.H. and A.S. (1143105), Program Grant to A.S. (1016701); the Leukemia and Lymphoma Society of America to A.S. and M.J.H. (LLS SCOR 7001-13); the Cancer Council of Victoria Project grant to A.S. (1052309) and Venture Grant to M.J.H. and A.S.; support to A.S. from the estate of Anthony (Toni) Redstone OAM and a Spanish Ministry of Economy and Development Grant to A.J. (RTI2018-099017-A-I00). K.D.S. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship (18003) and the Peter and Julie Alston Centenary Fellowship, A.J. is supported by Ramon y Cajal Fellowship (RYC2018-025244-I), A.S. and M.J.H. are supported by NHMRC Fellowships (1020363 and 1156095), M.S.B is supported by Cancer Council Victoria Postdoctoral Fellowship. This work was made possible through the Victorian Government Operational Infrastructure Support and Australian Government, a "Maria de Maeztu" Programme for Units of Excellence in R&D MDM-2014-0370 (Government of Spain) and La Caixa banking foundation (51110009).