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Updated: Jul 24, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a
Adam J Sugarman1, Luong Do Huynh1, Aidin Shabro1
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Abstract:
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.
Insights
Anaplastic thyroid cancer cells rely on one-carbon metabolism for growth. Inhibiting the enzyme SHMT2 starves these aggressive cancer cells of glycine, halting proliferation and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Anaplastic thyroid cancer (ATC) is highly aggressive, lethal, and resistant to conventional therapies.
- Key characteristics include dedifferentiation, epithelial-to-mesenchymal transition, and rapid proliferation.
- Identifying novel therapeutic targets is critical for improving patient outcomes.
Purpose of the Study:
- To identify novel, targetable molecular alterations in anaplastic thyroid cancer.
- To investigate the role of one-carbon metabolism in ATC pathogenesis and proliferation.
- To evaluate SHMT2 as a potential therapeutic target in ATC.
Main Methods:
- Analysis of gene expression profiles from an engineered mouse model and human ATC patient datasets.
- Genetic and pharmacological inhibition of serine hydroxymethyltransferase 2 (SHMT2).
- Assessment of cell proliferation, colony formation, and tumor growth in vitro and in vivo (xenograft and allograft models).
Main Results:
- Consistent upregulation of one-carbon metabolic pathway enzymes, including SHMT2, was observed in ATC.
- SHMT2 inhibition led to glycine auxotrophy, reduced proliferation, and impaired colony formation due to purine pool depletion.
- SHMT2 depletion significantly inhibited tumor growth in both xenograft and immunocompetent allograft models.
Conclusions:
- Upregulation of the one-carbon metabolic pathway is a novel vulnerability in anaplastic thyroid cancer.
- Targeting SHMT2 represents a promising therapeutic strategy for ATC.
- Inhibition of SHMT2 effectively suppresses ATC cell growth and tumor progression.
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