title: SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance.
abstract: Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Dohoon
authors: D
authors: Kim
authors: 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Brian P
authors: BP
authors: Fiske
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Kivanc
authors: K
authors: Birsoy
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Elizaveta
authors: E
authors: Freinkman
authors: Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan.
authors: Kenjiro
authors: K
authors: Kami
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Richard L
authors: RL
authors: Possemato
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Yakov
authors: Y
authors: Chudnovsky
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [6] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Michael E
authors: ME
authors: Pacold
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Walter W
authors: WW
authors: Chen
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Jason R
authors: JR
authors: Cantor
authors: Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA.
authors: Laura M
authors: LM
authors: Shelton
authors: 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Dan Y
authors: DY
authors: Gui
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA.
authors: Manjae
authors: M
authors: Kwon
authors: 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Shakti H
authors: SH
authors: Ramkissoon
authors: 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors: Keith L
authors: KL
authors: Ligon
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Seong Woo
authors: SW
authors: Kang
authors: Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA.
authors: Matija
authors: M
authors: Snuderl
authors: 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors: Matthew G
authors: MG
authors: Vander Heiden
authors: 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: David M
authors: DM
authors: Sabatini
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D005998:Glycine / Q000378:metabolism*; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000037:antagonists & inhibitors / Q000378:metabolism; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009336:Necrosis; D010101:Oxygen Consumption; D011765:Pyruvaldehyde / Q000378:metabolism / Q000633:toxicity; D011770:Pyruvate Kinase / Q000378:metabolism; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000096:Acetone; D011765:Pyruvaldehyde; D050841:Glycine Dehydrogenase (Decarboxylating); D012696:Glycine Hydroxymethyltransferase; D011770:Pyruvate Kinase; D005998:Glycine; C006495:aminoacetone