Mitonuclear genotype remodels the metabolic and microenvironmental landscape of Hürthle cell carcinoma
Ian Ganly, Eric Minwei Liu, Fengshen Kuo, Vladimir Makarov, Yiyu Dong, Jinsung Park, Yongxing Gong, Alexander N. Gorelick, Jeffrey A. Knauf, Elisa Benedetti, Jacqueline Tait-Mulder, Luc G.T. Morris, James A. Fagin, Andrew M. Intlekofer, Jan Krumsiek, Payam A. Gammage, Ronald Ghossein, Bin Xu, Timothy A. Chan, Ed Reznik
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.