An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. (February 2018)

• Record Type: Journal Article
• Authors: Chen, Ming; Zhang, Jiangwen; Sampieri, Katia; Clohessy, John; Mendez, Lourdes; Gonzalez-Billalabeitia, Enrique; Liu, Xue-Song; Lee, Yu-Ru; Fung, Jacqueline; Katon, Jesse; Menon, Archita; Webster, Kaitlyn; Ng, Christopher; Palumbieri, Maria; Diolombi, Moussa; Breitkopf, Susanne; Teruya-Feldstein, Julie; Signoretti, Sabina; Bronson, Roderick; Asara, John; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Pandolfi, Pier
• Is Part Of: Nature genetics. Volume 50:Number 2(2018)
• Page Start: 206
• Page End: 218
• Publication Date: 2018-02
• Subjects: Human genetics -- Periodicals; 576.505
• DOI: 10.1038/s41588-017-0027-2
• Languages: English
• ISSNs: 1061-4036

Abstract

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.