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Supplementary Figures S1-S9, Supplementary Table S1 from Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition

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posted on 2023-04-03, 22:44 authored by Bryan Ngo, Eugenie Kim, Victoria Osorio-Vasquez, Sophia Doll, Sophia Bustraan, Roger J. Liang, Alba Luengo, Shawn M. Davidson, Ahmed Ali, Gino B. Ferraro, Grant M. Fischer, Roozbeh Eskandari, Diane S. Kang, Jing Ni, Ariana Plasger, Vinagolu K. Rajasekhar, Edward R. Kastenhuber, Sarah Bacha, Roshan K. Sriram, Benjamin D. Stein, Samuel F. Bakhoum, Matija Snuderl, Paolo Cotzia, John H. Healey, Nello Mainolfi, Vipin Suri, Adam Friedman, Mark Manfredi, David M. Sabatini, Drew R. Jones, Min Yu, Jean J. Zhao, Rakesh K. Jain, Kayvan R. Keshari, Michael A. Davies, Matthew G. Vander Heiden, Eva Hernando, Matthias Mann, Lewis C. Cantley, Michael E. Pacold

Supplementary Figures and a Supplementary Table

Funding

NIH

Career Transition Fellowship

NRSA

NSF

MSKCC

NCI

Department of Defense

DOD

CPRIT

U.S. Department of Defense

Stand Up To Cancer

European Union

European Commission 7th Research Framework Program

Novo Nordisk Foundation

Mary Kay Foundation

Hearst Foundations

NYU

MRA

PHGDH

Stiftelsen Aust-Agder Utviklings- og Kompetansefond

History

ARTICLE 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. 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.This article is highlighted in the In This Issue feature, p. 1241

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    Cancer Discovery

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    Keywords

    Breast CancerDrug TargetsProgression, Invasion & MetastasisSmall Molecule AgentsTumor Microenvironment

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