Journal
CANCER DISCOVERY
Volume 10, Issue 9, Pages 1352-1373Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-1228
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Funding
- National Science Foundation (NSF) Graduate Research Fellowship
- NCI of the NIH [F99/K00, F99CA234950, R03 DA034602-01A1, R01 CA129105, R01 CA103866, R37 AI047389]
- NIH F31 Ruth L. Kirschstein National Research Service Award (NRSA) Pre-doctoral Fellowship [F31 CA250364-01]
- NSF Graduate Research Fellowship
- HHMI Medical Fellows Program
- Tow Foundation Postdoctoral Fellowship from the Center for Molecular Imaging and Nanotechnology (CMINT) at Memorial Sloan Kettering
- NIH National Center for Advancing Translational Sciences [TL1TR000369, UL1TR000371]
- University of Texas MD Anderson Cancer Center (MD Anderson)/UTHealth Graduate School of Biomedical Sciences' Caroline Ross Fellowship
- Schissler Foundation Fellowship
- Presidents' Research Scholarship
- MSKCC NIH/NCI Cancer Center Support Core Grant [P30-CA008748]
- NIH [DP5OD026395, R35 CA210057, P50 CA168504, R01CA237466, R01CA252037, R21CA212958, R21CA198028, R01CA168653, NCI R35CA197588, U54 CA210184]
- Department of Defense Breast Cancer Research Breakthrough Award [W81XWH-16-1-0315, BC151244]
- Burroughs Wellcome Fund Career Award for Medical Scientists
- Parker Institute for Immunotherapy at MSKCC
- Josie Robertson Foundation
- MSKCC core grant [P30-CA008748]
- NCI K22 Career Transition Award [K22 CA175228-01A1, 1K22CA212059]
- NIH DP2 award [DP2 CA206653]
- Donald E. And Delia B. Baxter Foundation
- Stop Cancer Foundation
- Wright Foundation
- DoD [W81XWH-18-1-0491]
- Breast Cancer Research Foundation
- STARR Cancer Consortium
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma Foundation
- NIH/NCI [R01 CA121118-06A1, 2T32CA009666-21, R01CA2022027, P01CA206980, 5P30CA016087]
- Cancer Prevention Research Institute of Texas (CPRIT) [RP170401, RP160183]
- MD Anderson Multidisciplinary Research Program
- Dana-Farber Harvard Cancer Center/MIT Koch Institute Bridge Project grant
- Lustgarten Foundation
- Ludwig Center at Harvard
- NCI [P01 CA080124, R01 CA126642, R01 CA085140, R01 CA115767, R01 CA098706, R01 CA208205, U01 CA224173, R35 CA197743]
- U.S. Department of Defense Breast Cancer Research Program Innovator Award [W81XWH-10-1-0016]
- MIT Ludwig Center
- MIT Center for Precision Cancer Medicine
- Stand Up To Cancer Innovative Research Grant [SU2C-AACR-IRG-09-16]
- HHMI
- NIH Melanoma SPORE [1P50CA225450]
- Max Planck Society for the Advancement of Science
- European Union's Horizon 2020 research and innovation program [686547]
- European Commission 7th Research Framework Program [ERC-202120Syg_318987]
- Novo Nordisk Foundation [NNF15CC0001]
- Gray Foundation Basser Initiative
- Mary Kay Foundation Cancer Research Grant [017-32]
- Shifrin-Myers Breast Cancer Discovery Fund at NYULMC
- V Foundation V Scholar Grant - Hearst Foundation [V2017-004]
- Career Enhancement Program Grant from the NYU Melanoma SPORE [1P50CA225450]
- Tara Miller Melanoma Foundation -MRA Young Investigator Award [MRA YIA 688365]
- John and Elaine Kanas Family Foundation
- NYUPCC Cancer Support Grant
- NYU Center for Bio-specimen Research and Development
- Roger and Susan Hertog Charitable Fund
- [T32GM007287]
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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.
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