Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.
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Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis.
Published Version (Please cite this version)10.1172/jci99699
Publication InfoChen, Ming; Zhang, Jiangwen; Berger, Alice H; Diolombi, Moussa S; Ng, Christopher; Fung, Jacqueline; ... Pandolfi, Pier Paolo (2019). Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. The Journal of clinical investigation, 129(1). pp. 215-222. 10.1172/jci99699. Retrieved from https://hdl.handle.net/10161/18169.
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Assistant Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long