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Nat Genet. 2018 Feb;50(2):206-218. doi: 10.1038/s41588-017-0027-2. Epub 2018 Jan 15.

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
2
School of Biological Sciences, University of Hong Kong, Hong Kong, China.
3
GSK Vaccines, Antigen Identification and Molecular Biology, Siena, Italy.
4
Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
5
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
6
Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
7
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
9
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
10
Department of Pathology, Champalimaud Center for the Unknown, Lisbon, Portugal.
11
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. ppandolf@bidmc.harvard.edu.

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.

PMID:
29335545
DOI:
10.1038/s41588-017-0027-2

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