3 years ago

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer
Jacqueline Fung, Kaitlyn A. Webster, Roderick T. Bronson, Moussa S. Diolombi, Jiangwen Zhang, Yu-Ru Lee, Susanne B. Breitkopf, Maria Dilia Palumbieri, Christopher Ng, Archita Venugopal Menon, Lourdes Mendez, Pier Paolo Pandolfi, Carlos Cordon-Cardo, Mireia Castillo-Martin, Julie Teruya-Feldstein, John G. Clohessy, John M. Asara, Katia Sampieri, Enrique Gonzalez-Billalabeitia, Ming Chen, Xue-Song Liu, Sabina Signoretti, Jesse M. Katon
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.

Publisher URL: https://www.nature.com/articles/s41588-017-0027-2

DOI: 10.1038/s41588-017-0027-2

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