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

  • Nat Commun. 2024 Feb 8;15(1):1163. doi: 10.1038/s41467-024-45366-0.
Seong Eun Lee  #  1  2 ,  Seongyeol Park  #  3  4 ,  Shinae Yi  1  2 ,  Na Rae Choi  1  2 ,  Mi Ae Lim  2  5 ,  Jae Won Chang  5 ,  Ho-Ryun Won  5 ,  Je Ryong Kim  6 ,  Hye Mi Ko  6 ,  Eun-Jae Chung  7 ,  Young Joo Park  8 ,  Sun Wook Cho  8 ,  Hyeong Won Yu  9 ,  June Young Choi  9 ,  Min-Kyung Yeo  10 ,  Boram Yi  3 ,  Kijong Yi  3 ,  Joonoh Lim  3 ,  Jun-Young Koh  3 ,  Min Jeong Lee  11 ,  Jun Young Heo  11 ,  Sang Jun Yoon  12 ,  Sung Won Kwon  12 ,  Jong-Lyul Park  13 ,  In Sun Chu  13  14 ,  Jin Man Kim  10 ,  Seon-Young Kim  13  14  15 ,  Yujuan Shan  16 ,  Lihua Liu  16 ,  Sung-A Hong  17 ,  Dong Wook Choi  18 ,  Junyoung O Park  19 ,  Young Seok Ju  3  20 ,  Minho Shong  20 ,  Seon-Kyu Kim  21 ,  Bon Seok Koo  22  23 ,  Yea Eun Kang  24  25  26
Affiliations
  • 1. Research Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 2. Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 3. GENOME INSIGHT TECHNOLOGY Inc, Daejeon, Republic of Korea.
  • 4. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 5. Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 6. Department of Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 7. Department of Otolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 8. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 9. Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea.
  • 10. Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 11. Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
  • 12. College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 13. Korea Research Institute of Bioscience and Biotechnology, Deajeon, Republic of Korea.
  • 14. Department of Bioscience, University of Science and Technology (UST), Deajeon, Republic of Korea.
  • 15. Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • 16. Department of Nutrition, School of Public Health and Management, Wenzhou Medical University, Wenzhou, 325035, China.
  • 17. Department of Biochemistry, Chungnam National University, Daejeon, Republic of Korea.
  • 18. Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
  • 19. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, USA.
  • 20. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • 21. Korea Research Institute of Bioscience and Biotechnology, Deajeon, Republic of Korea. [email protected].
  • 22. Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 23. Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 24. Research Center for Endocrine and Metabolic Disease, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 25. Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • 26. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 38331894 DOI: 10.1038/s41467-024-45366-0
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.