An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

Ming Chen; Jiangwen Zhang; Katia Sampieri; John G. Clohessy; Lourdes Mendez; Enrique Gonzalez-Billalabeitia; Xue Song Liu; Yu Ru Lee; Jacqueline Fung; Jesse M. Katon; Archita Venugopal Menon; Kaitlyn A. Webster; Christopher Ng; Maria Dilia Palumbieri; Moussa S. Diolombi; Susanne B. Breitkopf; Julie Teruya-Feldstein; Sabina Signoretti; Roderick T. Bronson; John M. Asara; Mireia Castillo-Martin; Carlos Cordon-Cardo; Pier Paolo Pandolfi

doi:10.1038/s41588-017-0027-2

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

Ming Chen, Jiangwen Zhang, Katia Sampieri, John G. Clohessy, Lourdes Mendez, Enrique Gonzalez-Billalabeitia, Xue Song Liu, Yu Ru Lee, Jacqueline Fung, Jesse M. Katon, Archita Venugopal Menon, Kaitlyn A. Webster, Christopher Ng, Maria Dilia Palumbieri, Moussa S. Diolombi, Susanne B. Breitkopf, Julie Teruya-Feldstein, Sabina Signoretti, Roderick T. Bronson, John M. AsaraMireia Castillo-Martin, Carlos Cordon-Cardo, Pier Paolo Pandolfi

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234 Scopus citations

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.

Original language	English
Pages (from-to)	206-218
Number of pages	13
Journal	Nature Genetics
Volume	50
Issue number	2
DOIs	https://doi.org/10.1038/s41588-017-0027-2
State	Published - 1 Feb 2018

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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., ... Pandolfi, P. P. (2018). An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nature Genetics, 50(2), 206-218. https://doi.org/10.1038/s41588-017-0027-2

@article{de3d4741da134080b2dbe9725ef810a5,

title = "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.",

author = "Ming Chen and Jiangwen Zhang and Katia Sampieri and Clohessy, {John G.} and Lourdes Mendez and Enrique Gonzalez-Billalabeitia and Liu, {Xue Song} and Lee, {Yu Ru} and Jacqueline Fung and Katon, {Jesse M.} and Menon, {Archita Venugopal} and Webster, {Kaitlyn A.} and Christopher Ng and Palumbieri, {Maria Dilia} and Diolombi, {Moussa S.} and Breitkopf, {Susanne B.} and Julie Teruya-Feldstein and Sabina Signoretti and Bronson, {Roderick T.} and Asara, {John M.} and Mireia Castillo-Martin and Carlos Cordon-Cardo and Pandolfi, {Pier Paolo}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = feb,

day = "1",

doi = "10.1038/s41588-017-0027-2",

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Chen, M, Zhang, J, Sampieri, K, Clohessy, JG, Mendez, L, Gonzalez-Billalabeitia, E, Liu, XS, Lee, YR, Fung, J, Katon, JM, Menon, AV, Webster, KA, Ng, C, Palumbieri, MD, Diolombi, MS, Breitkopf, SB, Teruya-Feldstein, J, Signoretti, S, Bronson, RT, Asara, JM, Castillo-Martin, M, Cordon-Cardo, C & Pandolfi, PP 2018, 'An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer', Nature Genetics, vol. 50, no. 2, pp. 206-218. https://doi.org/10.1038/s41588-017-0027-2

TY - JOUR

T1 - An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

AU - Chen, Ming

AU - Zhang, Jiangwen

AU - Sampieri, Katia

AU - Clohessy, John G.

AU - Mendez, Lourdes

AU - Gonzalez-Billalabeitia, Enrique

AU - Liu, Xue Song

AU - Lee, Yu Ru

AU - Fung, Jacqueline

AU - Katon, Jesse M.

AU - Menon, Archita Venugopal

AU - Webster, Kaitlyn A.

AU - Ng, Christopher

AU - Palumbieri, Maria Dilia

AU - Diolombi, Moussa S.

AU - Breitkopf, Susanne B.

AU - Teruya-Feldstein, Julie

AU - Signoretti, Sabina

AU - Bronson, Roderick T.

AU - Asara, John M.

AU - Castillo-Martin, Mireia

AU - Cordon-Cardo, Carlos

AU - Pandolfi, Pier Paolo

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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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U2 - 10.1038/s41588-017-0027-2

DO - 10.1038/s41588-017-0027-2

M3 - Article

C2 - 29335545

AN - SCOPUS:85040653917

SN - 1061-4036

VL - 50

SP - 206

EP - 218

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer

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