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

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Date
2018-02
Authors
Chen, Ming
Zhang, Jiangwen
Sampieri, Katia
Clohessy, John G
Mendez, Lourdes
Gonzalez-Billalabeitia, Enrique
Liu, Xue-Song
Lee, Yu-Ru
Fung, Jacqueline
Katon, Jesse M
Menon, Archita Venugopal
Webster, Kaitlyn A
Ng, Christopher
Palumbieri, Maria Dilia
Diolombi, Moussa S
Breitkopf, Susanne B
Teruya-Feldstein, Julie
Signoretti, Sabina
Bronson, Roderick T
Asara, John M
Castillo-Martin, Mireia
Cordon-Cardo, Carlos
Pandolfi, Pier Paolo
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(23 total)
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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 article
Subject
Cell Line, Tumor
Animals
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
Permalink
https://hdl.handle.net/10161/20378
Published Version (Please cite this version)
10.1038/s41588-017-0027-2
Publication 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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Scholars@Duke

Chen

Ming Chen

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
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