SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Authors: Dohoon Kim
Elizaveta Freinkman
Keith L Ligon
Shakti H Ramkissoon
Manjae Kwon
Brian P Fiske
Matthew G Vander Heiden
Matija Snuderl
Richard L Possemato
Yakov Chudnovsky
Walter W Chen
Michael E Pacold
Kenjiro Kami
Laura M Shelton
Seong Woo Kang
Dan Y Gui
David M Sabatini
Kivanc Birsoy
Jason R Cantor
Journal: Nature (2015)
Discipline: Multidisciplinary
Keywords: Cancer cells; metabolic processes; cell survival; tumour microenvironment; serine
Affiliations: 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., 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., Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan., 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., Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA., 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., 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., Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA., 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.

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. 

Retracted: No

PubPeer comments:
 In Supplemental Table 8 (Summary - peak areas), the data regarding citrate mass isotopomers M0 and M5 are the same for some u2013 but not for all u2013 conditions. Could the authors check if this is expected correct?  , 
 Dear Festuca Letourneuxiana, I have looked into this in conjunction with the corresponding author for this paper (David Sabatini), his former post-doc (Dohoon Kim) and my former student (Brian Fiske) who helped generate and analyze the mass spectrometry data included in the paper. The data in question from Supplemental Table 8 was provided with the paper, along with all of the raw LCMS data collected as part of these experiments, to make as much raw LCMS data available for use by the community (this is now standard practice, although it was not standard practice at the time this paper was published). These data include almost 10000 data points, and based on this query we went back and found 93 of 111 samples show pairs of Citrate m+0 and m+5 peaks that were reported as identical values, including some data where unlabeled citrate was run as a standard. Of the 18 of 111 remaining samples without equal m+0 and m+5 values, 10 show m+0 and m+5 values reported as NF (peak not found), while the remaining 8 show different m+0 and m+5 values and in all cases the m+5 value is slightly higher than m+0. Since the standard curve without labeled citrate shows anomalous  equal citrate m+0 and m+5 values, the citrate m+5 data is likely an error from the automated peak picking software Given the strict equality of the m+0 and m+5 values across 93 of 111 samples, and the small difference with an ordering of m+5 m+0 across the remaining 8 samples with reported values, most likely the same peak for m+5 was picked as for m+0 by the processing software with a slightly different but ultimately broader time and or mass window, causing a minority (8 of 110) of samples to report a slightly higher m+5 than m+0 value with others showing the same value. This would suggest the citrate m+5 raw data in this dataset is unreliable. Of relevance to the paper and the conclusions drawn, the citrate m+5 data was not used to generate the standard curve, and it was not included in any of the figures, text, or analyses reported in the paper (the relevant species for the paper was the m+2 species). All mass spectrometry experiments generate large amounts of data, much of which is never reported or available even with the more current standards of providing raw data. As a group, we feel strongly that data should be shared for both full transparency and to ensure that the work we did can help as many groups as possible. A downside of doing this is that it is impractical for anyone to manually curate all peaks across the large amount of mass spectrometry data generated, and occasionally some peaks will be unreliable as is the case here (and should be apparent to other groups who have experience analyzing this type of data). We of course manually check all peaks that affect the conclusions of the study being reported, but as outlined above the m+5 citrate species was not relevant for this study and therefore the peaks for those date were not manually curated. If you are interested in m+5 labeled citrate from glucose, I would have expected it to be a minor species and the peak picking error is almost certainly because it is only present in very low abundance. Nevertheless, if your research would benefit from a more reliable analysis of what is there, please contact me or the corresponding author through email and we are happy to look further to see if reliable data for this species can be extracted from the raw data, or provide you with the raw mass spectrometry data files if you have ability to process and analyze the data yourself. I am also open to collaborations if more directed experiments are needed to address your research question as I fear there may be not enough m+5 citrate labeling in these experiments to draw clear conclusions. Best, Matt Vander Heiden , 
  The authors declare no competing financial interests. However, a patent was submitted on 2012-02-10 (Inventors: Dohoon Kim, David M. Sabatini and Richard Possemato) entitled  Inhibition of the glycine cleavage system for treatment of cancer https: patents.google.com patent US9493775B2 According to Nature Research guidelines:  For patents and patent applications, disclosure of the following information is requested: patent applicant (whether author or institution), name of inventor(s), application number, status of application, specific aspect of manuscript covered in patent application. https: www.nature.com nature-research editorial-policies competing-interests  ,