Imaging Mass Spectrometry Reveals Tumor Metabolic Heterogeneity
Yang Zhang,
Christelle Guillermier,
Thomas De Raedt,
Andrew G. Cox,
Ophelia Maertens,
Dean Yimlamai,
Mingyue Lun,
Adam Whitney,
Richard L. Maas,
Wolfram Goessling,
Karen Cichowski,
Matthew L. Steinhauser
Affiliations
Yang Zhang
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Christelle Guillermier
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Thomas De Raedt
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Andrew G. Cox
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Ophelia Maertens
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Dean Yimlamai
Harvard Medical School, Boston, MA, USA; Boston Children's Hospital, Boston, MA, USA
Mingyue Lun
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
Adam Whitney
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA
Richard L. Maas
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Wolfram Goessling
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Karen Cichowski
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Ludwig Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA
Matthew L. Steinhauser
Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding author
Summary: Malignant tumors exhibit high degrees of genomic heterogeneity at the cellular level, leading to the view that subpopulations of tumor cells drive growth and treatment resistance. To examine the degree to which tumors also exhibit metabolic heterogeneity at the level of individual cells, we employed multi-isotope imaging mass spectrometry (MIMS) to quantify utilization of stable isotopes of glucose and glutamine along with a label for cell division. Mouse models of melanoma and malignant peripheral nerve sheath tumors (MPNSTs) exhibited striking heterogeneity of substrate utilization, evident in both proliferating and non-proliferating cells. We identified a correlation between metabolic heterogeneity, proliferation, and therapeutic resistance. Heterogeneity in metabolic substrate usage as revealed by incorporation of glucose and glutamine tracers is thus a marker for tumor proliferation. Collectively, our data demonstrate that MIMS provides a powerful tool with which to dissect metabolic functions of individual cells within the native tumor environment.
