Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a critical targetable vulnerability

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine.Genetic and pharmacological inhibition of SHMT2, a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic depletion of SHMT2 dramatically impaired tumor growth in vivo, both in xenograft models and in an immunocompetent allograft model of ATC.Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes.

Automated summary

Anaplastic thyroid cancer (ATC) is an aggressive and lethal tumor, characterized by loss of differentiation, high proliferation rate, and resistance to therapy. The upregulation of the one-carbon metabolic pathway in ATC cells, which generates nucleotides and glycine, was identified as a vulnerability that can be targeted for therapy. Inhibition of the key enzyme SHMT2 in this pathway led to glycine auxotrophy and significant inhibition of cell proliferation, especially in the presence of physiological levels of folates.