Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer

Matthew J. Watt, Ashlee K. Clark, Luke A. Selth, Vanessa R. Haynes, Natalie Lister, Richard Rebello, Laura H. Porter, Birunthi Niranjan, Sarah T. Whitby, Jennifer Lo, Cheng Huang, Ralf B. Schittenhelm, Kimberley E. Anderson, Luc Furic, Poornima R. Wijayaratne, Maria Matzaris, Magdalene K. Montgomery, Melissa Papargiris, Sam Norden, Maria Febbraio & 4 others Gail P. Risbridger, Mark Frydenberg, Daniel K. Nomura, Renea A. Taylor

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

Original languageEnglish
Article numbereaau5758
Number of pages12
JournalScience Translational Medicine
Volume11
Issue number478
DOIs
Publication statusPublished - 6 Feb 2019

Cite this

Watt, Matthew J. ; Clark, Ashlee K. ; Selth, Luke A. ; Haynes, Vanessa R. ; Lister, Natalie ; Rebello, Richard ; Porter, Laura H. ; Niranjan, Birunthi ; Whitby, Sarah T. ; Lo, Jennifer ; Huang, Cheng ; Schittenhelm, Ralf B. ; Anderson, Kimberley E. ; Furic, Luc ; Wijayaratne, Poornima R. ; Matzaris, Maria ; Montgomery, Magdalene K. ; Papargiris, Melissa ; Norden, Sam ; Febbraio, Maria ; Risbridger, Gail P. ; Frydenberg, Mark ; Nomura, Daniel K. ; Taylor, Renea A. / Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. In: Science Translational Medicine. 2019 ; Vol. 11, No. 478.
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title = "Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer",
abstract = "Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.",
author = "Watt, {Matthew J.} and Clark, {Ashlee K.} and Selth, {Luke A.} and Haynes, {Vanessa R.} and Natalie Lister and Richard Rebello and Porter, {Laura H.} and Birunthi Niranjan and Whitby, {Sarah T.} and Jennifer Lo and Cheng Huang and Schittenhelm, {Ralf B.} and Anderson, {Kimberley E.} and Luc Furic and Wijayaratne, {Poornima R.} and Maria Matzaris and Montgomery, {Magdalene K.} and Melissa Papargiris and Sam Norden and Maria Febbraio and Risbridger, {Gail P.} and Mark Frydenberg and Nomura, {Daniel K.} and Taylor, {Renea A.}",
year = "2019",
month = "2",
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doi = "10.1126/scitranslmed.aau5758",
language = "English",
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journal = "Science Translational Medicine",
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Watt, MJ, Clark, AK, Selth, LA, Haynes, VR, Lister, N, Rebello, R, Porter, LH, Niranjan, B, Whitby, ST, Lo, J, Huang, C, Schittenhelm, RB, Anderson, KE, Furic, L, Wijayaratne, PR, Matzaris, M, Montgomery, MK, Papargiris, M, Norden, S, Febbraio, M, Risbridger, GP, Frydenberg, M, Nomura, DK & Taylor, RA 2019, 'Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer' Science Translational Medicine, vol. 11, no. 478, eaau5758. https://doi.org/10.1126/scitranslmed.aau5758

Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. / Watt, Matthew J.; Clark, Ashlee K.; Selth, Luke A.; Haynes, Vanessa R.; Lister, Natalie; Rebello, Richard; Porter, Laura H.; Niranjan, Birunthi; Whitby, Sarah T.; Lo, Jennifer; Huang, Cheng; Schittenhelm, Ralf B.; Anderson, Kimberley E.; Furic, Luc; Wijayaratne, Poornima R.; Matzaris, Maria; Montgomery, Magdalene K.; Papargiris, Melissa; Norden, Sam; Febbraio, Maria; Risbridger, Gail P.; Frydenberg, Mark; Nomura, Daniel K.; Taylor, Renea A.

In: Science Translational Medicine, Vol. 11, No. 478, eaau5758, 06.02.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer

AU - Watt, Matthew J.

AU - Clark, Ashlee K.

AU - Selth, Luke A.

AU - Haynes, Vanessa R.

AU - Lister, Natalie

AU - Rebello, Richard

AU - Porter, Laura H.

AU - Niranjan, Birunthi

AU - Whitby, Sarah T.

AU - Lo, Jennifer

AU - Huang, Cheng

AU - Schittenhelm, Ralf B.

AU - Anderson, Kimberley E.

AU - Furic, Luc

AU - Wijayaratne, Poornima R.

AU - Matzaris, Maria

AU - Montgomery, Magdalene K.

AU - Papargiris, Melissa

AU - Norden, Sam

AU - Febbraio, Maria

AU - Risbridger, Gail P.

AU - Frydenberg, Mark

AU - Nomura, Daniel K.

AU - Taylor, Renea A.

PY - 2019/2/6

Y1 - 2019/2/6

N2 - Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

AB - Metabolism alterations are hallmarks of cancer, but the involvement of lipid metabolism in disease progression is unclear. We investigated the role of lipid metabolism in prostate cancer using tissue from patients with prostate cancer and patient-derived xenograft mouse models. We showed that fatty acid uptake was increased in human prostate cancer and that these fatty acids were directed toward biomass production. These changes were mediated, at least partly, by the fatty acid transporter CD36, which was associated with aggressive disease. Deleting Cd36 in the prostate of cancer-susceptible Pten−/− mice reduced fatty acid uptake and the abundance of oncogenic signaling lipids and slowed cancer progression. Moreover, CD36 antibody therapy reduced cancer severity in patient-derived xenografts. We further demonstrated cross-talk between fatty acid uptake and de novo lipogenesis and found that dual targeting of these pathways more potently inhibited proliferation of human cancer-derived organoids compared to the single treatments. These findings identify a critical role for CD36-mediated fatty acid uptake in prostate cancer and suggest that targeting fatty acid uptake might be an effective strategy for treating prostate cancer.

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U2 - 10.1126/scitranslmed.aau5758

DO - 10.1126/scitranslmed.aau5758

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VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

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