Abstract
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.
Original language | English (US) |
---|---|
Pages (from-to) | 1352-1373 |
Number of pages | 22 |
Journal | Cancer discovery |
Volume | 10 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2020 |
ASJC Scopus subject areas
- Oncology
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In: Cancer discovery, Vol. 10, No. 9, 09.2020, p. 1352-1373.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Limited environmental serine and glycine confer brain metastasis sensitivity to PHGDH inhibition
AU - Ngo, Bryan
AU - Kim, Eugenie
AU - Osorio-Vasquez, Victoria
AU - Doll, Sophia
AU - Bustraan, Sophia
AU - Liang, Roger J.
AU - Luengo, Alba
AU - Davidson, Shawn M.
AU - Ali, Ahmed
AU - Ferraro, Gino B.
AU - Fischer, Grant M.
AU - Eskandari, Roozbeh
AU - Kang, Diane S.
AU - Ni, Jing
AU - Plasger, Ariana
AU - Rajasekhar, Vinagolu K.
AU - Kastenhuber, Edward R.
AU - Bacha, Sarah
AU - Sriram, Roshan K.
AU - Stein, Benjamin D.
AU - Bakhoum, Samuel F.
AU - Snuderl, Matija
AU - Cotzia, Paolo
AU - Healey, John H.
AU - Mainolfi, Nello
AU - Suri, Vipin
AU - Friedman, Adam
AU - Manfredi, Mark
AU - Sabatini, David M.
AU - Jones, Drew R.
AU - Yu, Min
AU - Zhao, Jean J.
AU - Jain, Rakesh K.
AU - Keshari, Kayvan R.
AU - Davies, Michael A.
AU - Vander Heiden, Matthew G.
AU - Hernando, Eva
AU - Mann, Matthias
AU - Cantley, Lewis C.
AU - Pacold, Michael E.
N1 - Funding Information: B. Ngo is supported by a National Science Foundation (NSF) Graduate Research Fellowship and the NCI of the NIH under the F99/K00 Career Transition Fellowship (F99CA234950). V. Osorio-Vasquez is supported by an NIH F31 Ruth L. Kirschstein National Research Service Award (NRSA) Pre-doctoral Fellowship (F31 CA250364-01). A. Luengo and S.M. Davidson were supported by an NSF Graduate Research Fellowship and T32GM007287. A. Ali is supported by the HHMI Medical Fellows Program. R. Eskandari is supported by a Tow Foundation Postdoctoral Fellowship from the Center for Molecular Imaging and Nanotechnology (CMINT) at Memorial Sloan Kettering. G.M. Fischer received research funding from the NIH National Center for Advancing Translational Sciences (TL1TR000369 and UL1TR000371) and The University of Texas MD Anderson Cancer Center (MD Anderson)/ UTHealth Graduate School of Biomedical Sciences’ Caroline Ross Fellowship, Schissler Foundation Fellowship, and Presidents’ Research Scholarship. J.H. Healey and V.K. Rajasekhar are supported by the MSKCC NIH/NCI Cancer Center Support Core Grant P30-CA008748. S.F. Bakhoum is supported by the NIH (DP5OD026395 High-Risk High-Reward Program), the Department of Defense Breast Cancer Research Breakthrough Award W81XWH-16-1-0315 (project: BC151244), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Immunotherapy at MSKCC, the Josie Robertson Foundation, and the MSKCC core grant P30-CA008748. M. Yu is supported by an NCI K22 Career Transition Award (K22 CA175228-01A1), NIH DP2 award (DP2 CA206653), Donald E. And Delia B. Baxter Foundation, Stop Cancer Foundation, and Wright Foundation, and is a Pew-Stewart Scholar for Cancer Research. J.J. Zhao is supported by the NIH (R35 CA210057, P50 CA168504), DoD (W81XWH-18-1-0491), and the Breast Cancer Research Foundation. D.M. Sabatini is supported by the NCI of the NIH under Award R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389. D.M. Sabatini is an investigator of the Howard Hughes Medical Institute. K.R. Keshari is supported by the NIH (R01CA237466, R01CA252037, and R21CA212958) and the STARR Cancer Consortium. M.A. Davies is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (R01 CA121118-06A1 and 2T32CA009666-21), the Cancer Prevention Research Institute of Texas (CPRIT; RP170401 and RP160183), the MD Anderson Multidisciplinary Research Program, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. R.K. Jain and M.G. Vander Heiden were supported by a Dana-Farber Harvard Cancer Center/MIT Koch Institute Bridge Project grant. R.K. Jain is also supported by the Lustgarten Foundation; a grant from the Ludwig Center at Harvard; NCI grants P01 CA080124, R01 CA126642, R01 CA085140, R01 CA115767, R01 CA098706, R01 CA208205, U01 CA224173, and R35 CA197743; and U.S. Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016. M.G. Vander Heiden is also supported by the NIH (R21CA198028, R01CA168653), the MIT Ludwig Center, the MIT Center for Precision Cancer Medicine, a Stand Up To Cancer Innovative Research Grant, grant number SU2C-AACR-IRG-09-16, the Lustgarten Foundation, and a Faculty Scholar Grant from HHMI. Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. The SU2C research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. E. Hernando is supported by the NIH/ NCI R01CA2022027. NIH/NCI P01CA206980 (principal investigators: Berwick, Thomas), and NIH Melanoma SPORE 1P50CA225450 (principal investigators: Osman, Weber). M. Mann is supported by the Max Planck Society for the Advancement of Science, the European Union’s Horizon 2020 research and innovation program (Grant agreement no. 686547; MSmed project), the European Commission 7th Research Framework Program (GA ERC-202120Syg_318987; ToPAG project), and by the Novo Nordisk Foundation for the Clinical Proteomics group (grant NNF15CC0001). L.C. Cantley is supported by the NIH (NCI R35CA197588 and U54 CA210184), the Breast Cancer Research Foundation, the Gray Foundation Basser Initiative, and gifts from the Lori and Zachary Schreiber Family and the Roger and Susan Hertog Charitable Fund. M.E. Pacold is supported by a Mary Kay Foundation Cancer Research Grant (017-32), the Shifrin-Myers Breast Cancer Discovery Fund at NYULMC, a V Foundation V Scholar Grant funded by the Hearst Foundation (V2017-004), an NCI K22 Career Transition Award (1K22CA212059), a Career Enhancement Program Grant from the NYU Melanoma SPORE (1P50CA225450; principal investigators: Osman, Weber), the Tara Miller Melanoma Foundation – MRA Young Investigator Award (MRA YIA 688365), and laboratory-directed research funding from the John and Elaine Kanas Family Foundation. The NYULMC CBRD, Metabolomics Core Resource Laboratory, and NYULMC Cores are partially funded by the NYUPCC Cancer Support Grant, NIH/NCI 5P30CA016087. The authors would like to thank all members of the Mann, Cantley, and Pacold Laboratories for critical feedback. We also thank Xin Li, Christopher Chin, and Miriam Sindelar for technical assistance, Tony T. Huang, Steven Gross, Lin Lin, Edouard Mullarky, and Costas Lyssiotis for helpful discussions and technical advice, and the NYULH, WCMC, and MSK Small Animal Imaging Cores for assistance with MRI and BLI. Wild-type (Addgene plasmid 154917) and codon-optimized PHGDH were a gift of R. Pos-semato (Addgene plasmids 154915, 154916). We thank Huiyong Zhao (MSK Antitumor Assessment Core) and Arsen Mamakhanyan for technical assistance with Hyperpolarizer experiments. We thank Nelson Moss for preconsented brain metastasis specimens under approved IRB (177-067). We thank Iman Osman for the gift of the 12-273 short-term culture melanoma cell line. We are grateful for support from Luis Chiriboga and the NYU Center for Bio-specimen Research and Development and the NYU Metabolomics Core Resource Laboratory in acquiring and analyzing data. Funding Information: B. Ngo is supported by a National Science Foundation (NSF) Graduate Research Fellowship and the NCI of the NIH under the F99/K00 Career Transition Fellowship (F99CA234950). V. Osorio-Vasquez is supported by an NIH F31 Ruth L. Kirschstein National Research Service Award (NRSA) Pre-doctoral Fellowship (F31 CA250364-01). A. Luengo and S.M. Davidson were supported by an NSF Graduate Research Fellowship and T32GM007287. A. Ali is supported by the HHMI Medical Fellows Program. R. Eskandari is supported by a Tow Foundation Postdoctoral Fellowship from the Center for Molecular Imaging and Nanotechnology (CMINT) at Memorial Sloan Kettering. G.M. Fischer received research funding from the NIH National Center for Advancing Translational Sciences (TL1TR000369 and UL1TR000371) and The University of Texas MD Anderson Cancer Center (MD Anderson)/ UTHealth Graduate School of Biomedical Sciences? Caroline Ross Fel-lowship, Schissler Foundation Fellowship, and Presidents? Research Scholarship. J.H. Healey and V.K. Rajasekhar are supported by the MSKCC NIH/NCI Cancer Center Support Core Grant P30-CA008748. S.F. Bakhoum is supported by the NIH (DP5OD026395 High-Risk High-Reward Program), the Department of Defense Breast Cancer Research Breakthrough Award W81XWH-16-1-0315 (project: BC151244), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Immunotherapy at MSKCC, the Josie Robertson Foundation, and the MSKCC core grant P30-CA008748. M. Yu is supported by an NCI K22 Career Transition Award (K22 CA175228-01A1), NIH DP2 award (DP2 CA206653), Donald E. And Delia B. Baxter Foun-dation, Stop Cancer Foundation, and Wright Foundation, and is a Pew-Stewart Scholar for Cancer Research. J.J. Zhao is supported by the NIH (R35 CA210057, P50 CA168504), DoD (W81XWH-18-1-0491), and the Breast Cancer Research Foundation. D.M. Sabatini is supported by the NCI of the NIH under Award R03 DA034602-01A1, R01 CA129105, R01 CA103866, and R37 AI047389. D.M. Sabatini is an investigator of the Howard Hughes Medical Institute. K.R. Keshari is supported by the NIH (R01CA237466, R01CA252037, and R21CA212958) and the STARR Cancer Consortium. M.A. Davies is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (R01 CA121118-06A1 and 2T32CA009666-21), the Cancer Prevention Research Institute of Texas (CPRIT; RP170401 and RP160183), the MD Anderson Multidis-ciplinary Research Program, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. R.K. Jain and M.G. Vander Heiden were supported by a Dana-Farber Harvard Cancer Center/MIT Koch Institute Bridge Project grant. R.K. Jain is also supported by the Lustgarten Foundation; a grant from the Ludwig Center at Harvard; NCI grants P01 CA080124, R01 CA126642, R01 CA085140, R01 CA115767, R01 CA098706, R01 CA208205, U01 CA224173, and R35 CA197743; and U.S. Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016. M.G. Vander Heiden is also supported by the NIH (R21CA198028, R01CA168653), the MIT Ludwig Center, the MIT Center for Precision Cancer Medi-cine, a Stand Up To Cancer Innovative Research Grant, grant number SU2C-AACR-IRG-09-16, the Lustgarten Foundation, and a Faculty Scholar Grant from HHMI. Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. The SU2C research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. E. Hernando is supported by the NIH/ NCI R01CA2022027. NIH/NCI P01CA206980 (principal investigators: Berwick, Thomas), and NIH Melanoma SPORE 1P50CA225450 (principal investigators: Osman, Weber). M. Mann is supported by the Max Planck Society for the Advancement of Science, the European Union?s Horizon 2020 research and innovation program (Grant agreement no. 686547; MSmed project), the European Commission 7th Research Framework Program (GA ERC-202120Syg_318987; ToPAG project), and by the Novo Nordisk Foundation for the Clinical Proteomics group (grant NNF15CC0001). L.C. Cantley is supported by the NIH (NCI R35CA197588 and U54 CA210184), the Breast Cancer Research Foundation, the Gray Foundation Basser Initiative, and gifts from the Lori and Zachary Schreiber Family and the Roger and Susan Hertog Charitable Fund. M.E. Pacold is supported by a Mary Kay Foundation Cancer Research Grant (017-32), the Shifrin-Myers Breast Cancer Discovery Fund at NYULMC, a V Foundation V Scholar Grant funded by the Hearst Foundation (V2017-004), an NCI K22 Career Transition Award (1K22CA212059), a Career Enhancement Program Grant from the NYU Melanoma SPORE (1P50CA225450; principal investi-gators: Osman, Weber), the Tara Miller Melanoma Foundation ? MRA Young Investigator Award (MRA YIA 688365), and laboratory-directed research funding from the John and Elaine Kanas Family Foundation. The NYULMC CBRD, Metabolomics Core Resource Laboratory, and NYULMC Cores are partially funded by the NYUPCC Cancer Support Grant, NIH/NCI 5P30CA016087. The authors would like to thank all members of the Mann, Cantley, and Pacold Laboratories for critical feedback. We also thank Xin Li, Christopher Chin, and Miriam Sindelar for technical assistance, Tony T. Huang, Steven Gross, Lin Lin, Edouard Mullarky, and Costas Lyssiotis for helpful discussions and technical advice, and the NYULH, WCMC, and MSK Small Animal Imaging Cores for assistance with MRI and BLI. Wild-type (Addgene plasmid 154917) and codon-optimized PHGDH were a gift of R. Pos-semato (Addgene plasmids 154915, 154916). We thank Huiyong Zhao (MSK Antitumor Assessment Core) and Arsen Mamakhanyan for technical assistance with Hyperpolarizer experiments. We thank Nelson Moss for preconsented brain metastasis specimens under approved IRB (177-067). We thank Iman Osman for the gift of the 12-273 short-term culture melanoma cell line. We are grateful for support from Luis Chiriboga and the NYU Center for Bio-specimen Research and Development and the NYU Metabolomics Core Resource Laboratory in acquiring and analyzing data. Funding Information: B. Ngo reports grants from NCI and grants from NSF during the conduct of the study. J. Ni reports personal fees from Geode Therapeutics (consulting) outside the submitted work. S.F. Bakhoum reports personal fees and other funding from Volastra Therapeutics Inc. (consultant, scientific advisory board, board of directors, founder equity) and personal fees from Sanofi (consulting) outside the submitted work. A. Friedman reports other funding from Raze Therapeutics, Inc. (equity holder) during the conduct of the study; and other funding from Raze Therapeutics (equity holder) outside the submitted work. M. Manfredi reports equity in a company that is developing one of the compounds in this publication. M. Yu reports grants from NIH, Donald E. And Delia B. Baxter Foundation, Stop Cancer Foundation, Wright Foundation, and Pew Charitable Trusts during the conduct of the study; and nonfinancial support from CanTraCer Biosciences M. Yu is the founder and president for Can-TraCer Biosciences and reports personal fees from Microsensor Labs (paid consultant) outside the submitted work. J.J. Zhao reports grants from NCI, DoD, and Breast Cancer Research Foundation during the conduct of the study; in addition, J.J. Zhao has a patent for DFCI 2103.001 pending; and is a cofounder and director of Crimson BioPharm Inc. and Geode Therapeutics Inc. R.K. Jain reports grants from NIH (R35-CA197742, R01-CA208205, U01-CA224173 and P01-CA080124), grants from National Foundation for Cancer Research, grants from The Ludwig Center at Harvard, grants from The Jane’s Trust Foundation, grants from The Advanced Medical Research Foundation, and grants from Koch Institute/DFHCC Bridge Grant during the conduct of the study; personal fees from Amgen (honorarium), Chugai (consultant fees), Ophthotech (consultant fees), Merck (consultant fees), SPARC (consultant fees), SynDevRx (consultant fees & equity), XTuit (consultant fees & equity), Enlight (equity), Accurius Therapeutics (member, scientific advisory board), Tekla Healthcare Investors (boards of Trustees), Tekla Life Sciences Investors (boards of trustees), Tekla Healthcare Opportunities Fund (boards of trustees), and Tekla World Healthcare Fund (boards of trustees) outside the submitted work. K.R. Keshari reports grants from NIH and grants from STARR Cancer Consortium during the conduct of the study; and personal fees from nVision imaging Technologies (scientific advisory board member) outside the submitted work. M.A. Davies reports grants from AstraZeneca, grants and personal fees from Roche/ Genentech and Sanofi-Aventis; and personal fees from Novartis, Array, and BMS outside the submitted work. M.G. Vander Heiden reports personal fees from Agios Pharmaceuticals (scientific advisory board), iTeos Therapeutics (scientific advisory board), Aeglea Biotherapeutics (scientific advisory board), and Auron Therapeutics (scientific advisory board) outside the submitted work. L.C. Cantley reports grants from the NCI, Breast Cancer Research Foundation, and The Gray Family Foundation during the conduct of the study; and personal fees from Petra Pharmaceuticals (founder and SAB and support for Cantley lab) and Volastra Pharmaceuticals (founder and SAB), and personal fees from Faeth (founder and SAB) outside the submitted work; in addition, L.C. Cantley has a patent for Docket 7252 pending (patent on PHGDH inhibitor not used in this study). M.E. Pacold reports grants from NCI, Mary Kay Foundation, Shifrin-Myers Breast Cancer Discovery Fund, V Foundation, NYU Melanoma SPORE, Melanoma Research Alliance, and John and Elaine Kanas Family Foundation during the conduct of the study; nonfinancial support and other from Raze Therapeutics (options); and personal fees from Thermo Fisher Scientific (travel funds) outside the submitted work; in addition, M.E. Pacold has a patent for US20180105508A1 issued, licensed, and with royalties paid from Raze Therapeutics (NCT-503, an earlier generation PHGDH inhibitor). M.E. Pacold is a consultant to and holds equity in Raze Therapeutics and is the recipient of travel funds from Thermo Fisher Scientific. Raze Therapeutics holds patents on compounds used in this work. No potential conflicts of interest were disclosed by other authors. Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2020/9
Y1 - 2020/9
N2 - A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.
AB - A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.
UR - http://www.scopus.com/inward/record.url?scp=85092694854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092694854&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-19-1228
DO - 10.1158/2159-8290.CD-19-1228
M3 - Article
C2 - 32571778
AN - SCOPUS:85092694854
SN - 2159-8274
VL - 10
SP - 1352
EP - 1373
JO - Cancer discovery
JF - Cancer discovery
IS - 9
ER -