TY - JOUR
T1 - A unique subset of glycolytic tumour-propagating cells drives squamous cell carcinoma
AU - Choi, Jee Eun
AU - Sebastian, Carlos
AU - Ferrer, Christina M.
AU - Lewis, Caroline A.
AU - Sade-Feldman, Moshe
AU - LaSalle, Thomas
AU - Gonye, Anna
AU - Lopez, Begona G.C.
AU - Abdelmoula, Walid M.
AU - Regan, Michael S.
AU - Cetinbas, Murat
AU - Pascual, Gloria
AU - Wojtkiewicz, Gregory R.
AU - Silveira, Giorgia G.
AU - Boon, Ruben
AU - Ross, Kenneth N.
AU - Tirosh, Itay
AU - Saladi, Srinivas V.
AU - Ellisen, Leif W.
AU - Sadreyev, Ruslan I.
AU - Benitah, Salvador Aznar
AU - Agar, Nathalie Y.R.
AU - Hacohen, Nir
AU - Mostoslavsky, Raul
N1 - We thank D. Lombard (University of Michigan) for the pTripZ-shSIRT6 construct, M. Weissenboeck (Institute of Molecular Pathology, Vienna) for the pMSCV-luc-PGK-Neo-IRES-eGFP construct, C. Benes (MGH Cancer Center) for the HSC2 cell line and P. Dotto (MGH Cutaneous Biology Department) for the SCC13 cell line. Human tumour-associated fibroblasts were a gift from S.A.B. (IRB, Spain). We also thank B. Berman, H. Cedar and T. Silva for providing the analysis on SIRT6 promoter methylation, and C. Villacorta-Martin for providing advice on scRNA-seq analysis. We thank all the members of the Mostoslavsky laboratory for helpful discussions and critical reading of the manuscript. We also thank the Flow Core facilities at the MGH Center for Regenerative medicine and at the MGH Department of Pathology. C.S. was supported by the Department of Defense Visionary Postdoctoral Award (CA120342) and is a recipient of the Marie Sklodowska-Curie Actions Individual Fellowship. R.M. is the Laurel Schwartz Endowed Chair in Oncology. This work was supported by National Institutes of Health grants R01CA175727, R01GM128448 and the Massachusetts Life Sciences Center (MLSC) Bits to Bytes Award (R.M.), and the Arthur, Sandra and Sarah Irving Fund for Gastrointestinal Immuno-Oncology (N.H.). Author contributions - J.-E.C. and R.M. conceptualized and designed the study; J-E.C. performed and analysed most of the experiments; J-E.C., C.S., and C.M.F. performed animal experiments; C.A.L. performed and analysed LC–MS metabolite assays; M.S-F., T.L., A.G., performed and analysed scRNA-seq with supervision of N.H.; B.G.C.L., W.M.A., and M.S.R. performed and analysed MALDI-MSI with supervision of N.Y.R.A.; M.C. and R.I.S. performed and analysed bulk RNA-seq; G.P. and S.A.B. designed xenotransplantation assays; G.R.W. performed and analysed bioluminescence imaging; J-E.C. and G.G.S. performed and analysed immunofluorescence imaging and western blot assays; R.B. performed and analysed gas chromatography–mass spectrometry assays; K.N.R. analysed the TCGA data; I.T. analysed scRNA-seq data from human HNSCC patient samples; S.V.S. and L.W.E. provided FFPE human samples for immunohistochemical analysis; J-E.C. and R.M. wrote the manuscript; R.M. supervised the project.
PY - 2021/2
Y1 - 2021/2
N2 - Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.
AB - Head and neck squamous cell carcinoma (SCC) remains among the most aggressive human cancers. Tumour progression and aggressiveness in SCC are largely driven by tumour-propagating cells (TPCs). Aerobic glycolysis, also known as the Warburg effect, is a characteristic of many cancers; however, whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase sirtuin 6 is a robust tumour suppressor in SCC, acting as a modulator of glycolysis in these tumours. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single-cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Together, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell of origin for the Warburg effect, defining metabolism as a key feature of intra-tumour heterogeneity.
UR - http://www.scopus.com/inward/record.url?scp=85101218537&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s42255-021-00350-6
DO - https://doi.org/10.1038/s42255-021-00350-6
M3 - مقالة
SN - 2522-5812
VL - 3
SP - 182
EP - 195
JO - Nature metabolism
JF - Nature metabolism
IS - 2
ER -