An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. (February 2018) - Chen, Ming
Abstract Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found thatPML is frequently co-deleted withPTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation ofPml in the mouse prostate morphs indolentPten -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 metastaticPml andPten 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 nonmetastaticPten -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. This study shows that inactivation ofPml in the mouse prostate turns indolentPten -null tumors into lethal metastatic disease. The authors identify an aberrant SREBP prometastatic lipogenic program and show that a high-fat diet induces lipid accumulation in prostate tumors and is sufficient to drive metastasis.