Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma

Ganly, I. et al. (2022) Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma. Science Advances, 8(25), eabn9699. (doi: 10.1126/sciadv.abn9699) (PMID:35731870) (PMCID:PMC9216518)

Abstract

Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). To understand the phenotypic consequences of these genetic alterations, we analyzed genomic, metabolomic, and immunophenotypic data of HCC and other thyroid cancers. Both mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment, whereas metabolites in the reduced form of NADH-dependent lysine degradation pathway were elevated exclusively in HCC. The presence of gLOH was not associated with metabolic phenotypes but rather with reduced immune infiltration, indicating that gLOH confers a selective advantage partially through immunosuppression. Unsupervised multimodal clustering revealed four clusters of HCC with distinct clinical, metabolomic, and microenvironmental phenotypes but overlapping genotypes. These findings chart the metabolic and microenvironmental landscape of HCC and shed light on the interaction between genotype, metabolism, and the microenvironment in cancer.

• Item Type: Articles
• Additional Information: This work was supported by the Geoffrey Beene Cancer Research Center Grant Award, Department of Defense Kidney Cancer Research Program (no. W81XWH-18-1-0318), Cycle For Survival Equinox Innovation Award, Kidney Cancer Association Young Investigator Award, Hutchison Shaw Foundation, Pechter Foundation, NIH SPORE grant (P50 CA172012-01A1), NIH/NCI Cancer Center Support Grant (P30 CA008748), and Core funding from CRUK BI (nos. A17196 and A31287).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gammage, Dr Payam and Tait-Mulder, Dr Jacqueline
• Authors: Ganly, I., Liu, E. M., Kuo, F., Makarov, V., Dong, Y., Park, J., Gong, Y., Gorelick, A. N., Knauf, J. A., Benedetti, E., Tait-Mulder, J., Morris, L. G.T., Fagin, J. A., Intlekofer, A. M., Krumsiek, J., Gammage, P. A., Ghossein, R., Xu, B., Chan, T. A., and Reznik, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Advances
• Publisher: American Association for the Advancement of Science
• ISSN: 2375-2548
• ISSN (Online): 2375-2548
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Science Advances 8(25):eabn9699
• Publisher Policy: Reproduced under a Creative Commons License