Browsing by Author "Zhang, Jiangwen"

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    An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.
    (Nature genetics, 2018-02) Chen, Ming; Zhang, Jiangwen; Sampieri, Katia; Clohessy, John G; Mendez, Lourdes; Gonzalez-Billalabeitia, Enrique; Liu, Xue-Song; Lee, Yu-Ru; Fung, Jacqueline; Katon, Jesse M; Menon, Archita Venugopal; Webster, Kaitlyn A; Ng, Christopher; Palumbieri, Maria Dilia; Diolombi, Moussa S; Breitkopf, Susanne B; Teruya-Feldstein, Julie; Signoretti, Sabina; Bronson, Roderick T; Asara, John M; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo
    Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.
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    Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis.
    (The Journal of clinical investigation, 2019-01) Chen, Ming; Zhang, Jiangwen; Berger, Alice H; Diolombi, Moussa S; Ng, Christopher; Fung, Jacqueline; Bronson, Roderick T; Castillo-Martin, Mireia; Thin, Tin Htwe; Cordon-Cardo, Carlos; Plevin, Robin; Pandolfi, Pier Paolo
    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.
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    Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.
    (Nature communications, 2018-01-15) Chen, Ming; Wan, Lixin; Zhang, Jiangwen; Zhang, Jinfang; Mendez, Lourdes; Clohessy, John G; Berry, Kelsey; Victor, Joshua; Yin, Qing; Zhu, Yuan; Wei, Wenyi; Pandolfi, Pier Paolo
    The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications.