Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses

Seong Eun Lee, Seongyeol Park, Shinae Yi, Na Rae Choi, Mi Ae Lim, Jae Won Chang, Ho-Ryun Won, Je Ryong Kim, Hye Mi Ko, Eun-Jae Chung, Young Joo Park, Sun Wook Cho, Hyeong Won Yu, June Young Choi, Min-Kyung Yeo, Boram Yi, Kijong Yi, Joonoh Lim, Jun-Young Koh, Min Jeong Lee, Jun Young Heo, Sang Jun Yoon, Sung Won Kwon, Jong-Lyul Park, In Sun Chu, Jin Man Kim, Seon-Young Kim, Yujuan Shan, Lihua Liu, Sung-A Hong, Dong Wook Choi, Junyoung O. Park, Young Seok Ju, Minho Shong, Seon-Kyu Kim (), Bon Seok Koo () and Yea Eun Kang ()
Additional contact information
Seong Eun Lee: Chungnam National University
Seongyeol Park: GENOME INSIGHT TECHNOLOGY Inc
Shinae Yi: Chungnam National University
Na Rae Choi: Chungnam National University
Mi Ae Lim: Chungnam National University
Jae Won Chang: Chungnam National University
Ho-Ryun Won: Chungnam National University
Je Ryong Kim: Chungnam National University
Hye Mi Ko: Chungnam National University
Eun-Jae Chung: Seoul National University College of Medicine
Young Joo Park: Seoul National University College of Medicine
Sun Wook Cho: Seoul National University College of Medicine
Hyeong Won Yu: Seoul National University Bundang Hospital
June Young Choi: Seoul National University Bundang Hospital
Min-Kyung Yeo: Chungnam National University
Boram Yi: GENOME INSIGHT TECHNOLOGY Inc
Kijong Yi: GENOME INSIGHT TECHNOLOGY Inc
Joonoh Lim: GENOME INSIGHT TECHNOLOGY Inc
Jun-Young Koh: GENOME INSIGHT TECHNOLOGY Inc
Min Jeong Lee: Chungnam National University
Jun Young Heo: Chungnam National University
Sang Jun Yoon: Seoul National University
Sung Won Kwon: Seoul National University
Jong-Lyul Park: Korea Research Institute of Bioscience and Biotechnology
In Sun Chu: Korea Research Institute of Bioscience and Biotechnology
Jin Man Kim: Chungnam National University
Seon-Young Kim: Korea Research Institute of Bioscience and Biotechnology
Yujuan Shan: Wenzhou Medical University
Lihua Liu: Wenzhou Medical University
Sung-A Hong: Chungnam National University
Dong Wook Choi: Korea University
Junyoung O. Park: University of California, Los Angeles
Young Seok Ju: GENOME INSIGHT TECHNOLOGY Inc
Minho Shong: Korea Advanced Institute of Science and Technology
Seon-Kyu Kim: Korea Research Institute of Bioscience and Biotechnology
Bon Seok Koo: Chungnam National University
Yea Eun Kang: Chungnam National University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Date: 2024
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DOI: 10.1038/s41467-024-45366-0

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