An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.
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.
Chen, M; Zhang, J; Sampieri, K; Clohessy, JG; Mendez, L; Gonzalez-Billalabeitia, E; Liu, X-S; Lee, Y-R; Fung, J; Katon, JM; Menon, AV; Webster, KA; Ng, C; Palumbieri, MD; Diolombi, MS; Breitkopf, SB; Teruya-Feldstein, J; Signoretti, S; Bronson, RT; Asara, JM; Castillo-Martin, M; Cordon-Cardo, C; Pandolfi, PP
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