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.

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

Pandolfi P. P.
Last
2018

Abstract

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.
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http://www.nature.com/ng/index.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714980/
Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Humans; Lipogenesis; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Metastasis; PC-3 Cells; PTEN Phosphohydrolase; Prostatic Neoplasms; Sterol Regulatory Element Binding Proteins
Chen M.; Zhang J.; Sampieri K.; Clohessy J.G.; Mendez L.; Gonzalez-Billalabeitia E.; Liu X.-S.; Lee Y.-R.; Fung J.; Katon J.M.; Menon A.V.; Webster K.A.; Ng C.; Palumbieri M.D.; Diolombi M.S.; Breitkopf S.B.; Teruya-Feldstein J.; Signoretti S.; Bronson R.T.; Asara J.M.; Castillo-Martin M.; Cordon-Cardo C.; Pandolfi P.P.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1732871
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