An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.
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.
Type
Journal articleSubject
Cell Line, TumorAnimals
Mice, Inbred C57BL
Mice, Knockout
Humans
Mice
Prostatic Neoplasms
Cell Transformation, Neoplastic
Neoplasm Metastasis
Cell Proliferation
Male
Lipogenesis
PTEN Phosphohydrolase
Sterol Regulatory Element Binding Proteins
Metabolic Networks and Pathways
PC-3 Cells
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https://hdl.handle.net/10161/20378Published Version (Please cite this version)
10.1038/s41588-017-0027-2Publication Info
Chen, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Ming Chen
Associate 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

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