Identifying Metabolic Liabilities in Hürthle Cell Thyroid Carcinoma

A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. Hürthle cell carcinoma of the thyroid (HTC) represents an outlier wherein HTC tumors enrich for mitochondrial DNA mutations that are predicted to impair complex I of the electron transport chain (ETC). Consistent with these mutations, our work shows that HTC models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in central carbon metabolism. We investigated whether the metabolic adaptations to complex I deficiency constitute HTC-specific vulnerabilities that could be therapeutically targeted. Our initial studies demonstrated that aspartate biosynthesis, a key output of respiration in proliferation cells, was altered in complex I-deficient HTC cells. Genetic disruption of alternative aspartate biosynthetic pathways selectively impaired HTC cell growth in culture; however, inhibition of these pathways did not impair HTC growth in vivo. We utilized proliferation-based CRISPR-Cas9 pooled screening to identify additional HTC-specific metabolic liabilities and found that glycolytic enzymes are selectively essential in complex I-mutant HTC cells. The respiratory defects and shifts to glycolytic metabolism found in complex I-deficient HTC cells enforce a reliance on fermentation that is targetable with small molecule inhibitors of lactate dehydrogenase (LDH) both in cultured cells and in vivo models. Using forward genetic screens, we identified mechanisms of resistance to LDH inhibitor treatment including inhibitor-specific mutations and upregulation of LDH isoforms. Combined, this work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.

Author dc:creator

• Frank, Anderson Ross, IV

Contributors dc:contributor

• Tu, Benjamin
• DeBerardinis, Ralph J.
• Mishra, Prashant
• McFadden, David G.

• Adenoma, Oxyphilic
• Carcinoma
• DNA, Mitochondrial
• Thyroid Neoplasms
• Adenocarcinoma

Language dc:language

en

Identifier

1522122347

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10595