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
2018-01-01

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.
2018
50
2
206
218
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: https://hdl.handle.net/2318/1732871
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