Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1228
Entities
People
- Adam L. Friedman
- Ahmed Ali
- Alba Luengo
- Ariana Plasger
- Benjamin D. Stein
- Bryan Ngo
- David M. Sabatini
- Diane S. Kang
- Drew R Jones
- Edward R. Kastenhuber
- Eugenie Kim
- Eva Hernando
- Gino B. Ferraro
- Grant M. Fischer
- Jean J. Zhao
- Jing Ni
- John H. Healey
- Kayvan R. Keshari
- Lewis C. Cantley
- Mark Manfredi
- Matija Snuderl
- Matthew G Vander Heiden
- Matthias Mann
- Michael A Davies
- Michael E Pacold
- Min Yu
- Nello Mainolfi
- Paolo Cotzia
- Rakesh Jain
- Roger J. Liang
- Roozbeh Eskandari
- Roshan K. Sriram
- Samuel F Bakhoum
- Sarah Bacha
- Shawn M. Davidson
- Sophia Bustraan
- Sophia Doll
- Victoria Osorio-Vasquez
- Vinagolu K. Rajasekhar
- Vipin Suri
Organizations
- AIM at Melanoma Foundation
- Adelson Foundation
- American Association for Cancer Research
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- Dana–Farber Cancer Institute
- European Commission
- Harvard Medical School
- Howard Hughes Medical Institute
- Lustgarten Foundation for Pancreatic Cancer Research
- Mary Kay Foundation
- Massachusetts General Hospital
- Massachusetts Institute of Technology
- Max Planck Institute of Biochemistry
- Max Planck Society
- Melanoma Research Alliance
- Memorial Sloan Kettering Cancer Center
- NYU Langone Health
- National Cancer Institute
- National Center for Advancing Translational Sciences
- National Institutes of Health
- National Science Foundation
- New York University
- Novo Nordisk Fonden
- Princeton University
- The Breast Cancer Research Foundation
- The Pew Charitable Trusts
- The Starr Foundation
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense
- University of Copenhagen
- University of Southern California
- University of Texas at Austin
- V Foundation for Cancer Research
- Weill Cornell Medicine