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Nat. Commun., Feb 08 2024, 15 (1) 1163 | https://doi.org/10.1038/s41467-024-45366-0 Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses

Seong Eun Lee^1,2,22, Seongyeol Park^3,21,22, Shinae Yi^1,2, Na Rae Choi^1,2, Mi Ae Lim^2,4, Jae Won Chang⁴, Ho-Ryun Won⁴, Je Ryong Kim⁵, Hye Mi Ko⁵, Eun-Jae Chung⁶, Young Joo Park⁷, Sun Wook Cho⁷, Hyeong Won Yu⁸, June Young Choi⁸, Min-Kyung Yeo⁹, Boram Yi³, Kijong Yi³, Joonoh Lim³, Jun-Young Koh³, Min Jeong Lee¹⁰, Jun Young Heo¹⁰, Sang Jun Yoon¹¹, Sung Won Kwon¹¹, Jong-Lyul Park¹², In Sun Chu^12,13, Jin Man Kim⁹, Seon-Young Kim^12,13,14, Yujuan Shan¹⁵, Lihua Liu¹⁵, Sung-A Hong¹⁶, Dong Wook Choi¹⁷, Junyoung O. Park¹⁸, Young Seok Ju^3,19, Minho Shong¹⁹, Seon-Kyu Kim¹², Bon Seok Koo^2,4& Yea Eun Kang^1,2,20

¹Research Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

²Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

³GENOME INSIGHT TECHNOLOGY Inc, Daejeon, Republic of Korea.

⁴Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

⁵Department of Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

⁶Department of Otolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.

⁷Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

⁸Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.

⁹Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

¹⁰Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

¹¹College of Pharmacy, Seoul National University, Seoul, Republic of Korea.

¹²Korea Research Institute of Bioscience and Biotechnology, Deajeon, Republic of Korea.

¹³Department of Bioscience, University of Science and Technology (UST), Deajeon, Republic of Korea.

¹⁴Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.

¹⁵Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou 325035, China.

¹⁶Department of Biochemistry Chungnam National University, Daejeon, Republic of Korea.

¹⁷Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.

¹⁸Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, USA.

¹⁹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

²⁰Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

²¹Present address: Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.

²²These authors contributed equally: Seong Eun Lee, Seongyeol Park.

Corresponding authors : Correspondence to Seon-Kyu Kim, Bon Seok Koo or Yea Eun Kang.

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.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-14)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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