An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.
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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.
SubjectCell Line, Tumor
Mice, Inbred C57BL
Cell Transformation, Neoplastic
Sterol Regulatory Element Binding Proteins
Metabolic Networks and Pathways
Published Version (Please cite this version)10.1038/s41588-017-0027-2
Publication InfoChen, Ming; Zhang, Jiangwen; Sampieri, Katia; Clohessy, John G; Mendez, Lourdes; Gonzalez-Billalabeitia, Enrique; ... Pandolfi, Pier Paolo (2018). An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nature genetics, 50(2). pp. 206-218. 10.1038/s41588-017-0027-2. Retrieved from https://hdl.handle.net/10161/20378.
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Assistant Professor in Pathology
Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long