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Regulation of cancer stem cell activity by thyroid hormone receptor β

Abstract

Increasing numbers of cancer stem cell markers have been recently identified. It is not known, however, whether a member of the nuclear receptor superfamily, thyroid hormone receptor β (TRβ), can function to regulate cancer stem cell (CSC) activity. Using anaplastic thyroid cancer cells (ATC) as a model, we highlight the role of TRβ in CSC activity. ATC is one of the most aggressive solid cancers in humans and is resistant to currently available therapeutics. Recent studies provide evidence that CSC activity underlies aggressiveness and therapeutic resistance of ATC. Here we show that TRβ inhibits CSC activity by suppressing tumor-sphere formation of human ATC cells and their tumor-initiating capacity. TRβ suppresses the expression of CSC regulators, including ALDH, KLF2, SOX2, b-catenin, and ABCG2, in ATC cell-induced xenograft tumors. Single-cell transcriptomic analysis shows that TRβ reduces CSC population in ATC-induced xenograft tumors. Analysis of The Cancer Genome Atlas (TCGA) database demonstrates that the inhibition of CSC capacity by TRβ contributes to favorable clinical outcomes in human cancer. Our studies show that TRβ is a newly identified transcription regulator that acts to suppress CSC activity and that TRβ could be considered as a molecular target for therapeutic intervention of ATC.

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Fig. 1: ATC exhibits high stemness, thereby facilitating its initiation and growth.
Fig. 2: TRβ attenuates capacity of CSCs.
Fig. 3: TRβ blocks the tumor-initiating capacity of CSCs in ATC.
Fig. 4: TRβ reduces both capacity and population size of CSCs in vivo.
Fig. 5: T3 potentiates transcriptional inhibition of ALDH by TRβ in ATC cells.
Fig. 6: TRβ is negatively associated with cancer stemness.

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References

  1. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.

    Article  CAS  PubMed  Google Scholar 

  2. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.

    Article  CAS  PubMed  Google Scholar 

  4. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. nature. 2004;432:396–401.

    Article  CAS  PubMed  Google Scholar 

  5. Ayob AZ, Ramasamy TS. Cancer stem cells as key drivers of tumour progression. J Biomed Sci. 2018;25:20.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Tuttle RM, Haugen B, Perrier ND Updated American Joint Committee on cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer: what changed and why? Mary Ann Liebert, Inc. 140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA, 2017.

  7. Smallridge RC. Approach to the patient with anaplastic thyroid carcinoma. J Clin Endocrinol Metab. 2012;97:2566–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tiedje V, Stuschke M, Weber F, Dralle H, Moss L, Führer D. Anaplastic thyroid carcinoma: review of treatment protocols. Endocr-Relat cancer. 2018;25:R153–R161.

    Article  CAS  PubMed  Google Scholar 

  9. Molinaro E, Romei C, Biagini A, Sabini E, Agate L, Mazzeo S, et al. Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Nat Rev Endocrinol. 2017;13:644–60.

    Article  CAS  PubMed  Google Scholar 

  10. Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22:1104–39.

    Article  PubMed  Google Scholar 

  11. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36:7–13.

    Article  CAS  PubMed  Google Scholar 

  12. Lee WK, Lee SG, Yim SH, Kim D, Kim H, Jeong S, et al. Whole exome sequencing identifies a novel hedgehog-interacting protein g516r mutation in locally advanced papillary thyroid cancer. Int J Mol Sci. 2018;19:2867.

    Article  PubMed Central  Google Scholar 

  13. Ando S, Sarlis NJ, Oldfield EH, Yen PM. Somatic mutation of TRβ can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab. 2001;86:5572–6.

    CAS  PubMed  Google Scholar 

  14. Silva JM, Domínguez G, González-Sancho JM, García JM, Silva J, García-Andrade C, et al. Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer. Oncogene. 2002;21:4307.

    Article  CAS  PubMed  Google Scholar 

  15. Aranda A, Martínez-Iglesias O, Ruiz-Llorente L, García-Carpizo V, Zambrano A. Thyroid receptor: roles in cancer. Trends Endocrinol Metab. 2009;20:318–24.

    Article  CAS  PubMed  Google Scholar 

  16. Kim WG, Cheng S-Y. Thyroid hormone receptors and cancer. Biochimica et Biophysica Acta (BBA)-Gen Subj. 2013;1830:3928–36.

    Article  CAS  Google Scholar 

  17. Suzuki H, Willingham MC, Cheng S-Y. Mice with a mutation in the thyroid hormone receptor β gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid. 2002;12:963–9.

    Article  CAS  PubMed  Google Scholar 

  18. Li Z, Meng ZH, Chandrasekaran R, Kuo W-L, Collins CC, Gray JW, et al. Biallelic inactivation of the thyroid hormone receptor β1 gene in early stage breast cancer. Cancer Res. 2002;62:1939–43.

    CAS  PubMed  Google Scholar 

  19. Iwasaki Y, Sunaga N, Tomizawa Y, Imai H, Iijima H, Yanagitani N, et al. Epigenetic inactivation of the thyroid hormone receptor β1 gene at 3p24. 2 in lung cancer. Ann surgical Oncol. 2010;17:2222–8.

    Article  Google Scholar 

  20. Joseph B, Ji M, Liu D, Hou P, Xing M. Lack of mutations in the thyroid hormone receptor (TR) α and β genes but frequent hypermethylation of the TR β gene in differentiated thyroid tumors. J Clin Endocrinol Metab. 2007;92:4766–70.

    Article  CAS  PubMed  Google Scholar 

  21. Kim WG, Zhu X, Kim DW, Zhang L, Kebebew E, Cheng S-Y. Reactivation of the silenced thyroid hormone receptor β gene expression delays thyroid tumor progression. Endocrinology. 2013;154:25–35.

    Article  CAS  PubMed  Google Scholar 

  22. Jazdzewski K, Boguslawska J, Jendrzejewski J, Liyanarachchi S, Pachucki J, Wardyn KA, et al. Thyroid hormone receptor β (THRB) is a major target gene for microRNAs deregulated in papillary thyroid carcinoma (PTC). J Clin Endocrinol Metab. 2011;96:E546–E553.

    Article  CAS  PubMed  Google Scholar 

  23. Lee C-H, Yu C-C, Wang B-Y, Chang W-W. Tumorsphere as an effective in vitro platform for screening anti-cancer stem cell drugs. Oncotarget. 2016;7:1215.

    Article  PubMed  Google Scholar 

  24. Park JW, Zhao L, Cheng S-Y. Inhibition of estrogen-dependent tumorigenesis by the thyroid hormone receptor β in xenograft models. Am J cancer Res. 2013;3:302.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J immunological methods. 2009;347:70–78.

    Article  CAS  Google Scholar 

  26. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? cell stem cell. 2015;16:225–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mabbott NA, Baillie JK, Brown H, Freeman TC, Hume DA. An expression atlas of human primary cells: inference of gene function from coexpression networks. BMC genomics. 2013;14:1–13.

    Article  Google Scholar 

  28. Jean E, Laoudj‐Chenivesse D, Notarnicola C, Rouger K, Serratrice N, Bonnieu A, et al. Aldehyde dehydrogenase activity promotes survival of human muscle precursor cells. J Cell Mol Med. 2011;15:119–33.

    Article  PubMed  Google Scholar 

  29. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin cancer Res. 2009;15:4234–41.

    Article  CAS  PubMed  Google Scholar 

  30. Agrawal N, Akbani R, Aksoy BA, Ally A, Arachchi H, Asa SL, et al. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.

    Article  PubMed Central  Google Scholar 

  31. Li W, Reeb AN, Sewell WA, Elhomsy G, Lin RY. Phenotypic characterization of metastatic anaplastic thyroid cancer stem cells. PLoS One. 2013;8:e65095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bolf EL, Gillis NE, Davidson CD, Rodriguez PD, Cozzens L, Tomczak JA, et al. Thyroid hormone receptor beta induces a tumor-suppressive program in anaplastic thyroid cancer. Mol cancer Res: MCR. 2020;18:1443–52.

    Article  CAS  PubMed  Google Scholar 

  33. Haghpanah V, Fallah P, Naderi M, Tavakoli R, Soleimani M, Larijani B. Cancer stem-like cell behavior in anaplastic thyroid cancer: a challenging dilemma. Life Sci. 2016;146:34–39.

    Article  CAS  PubMed  Google Scholar 

  34. Lee WK, Cheng S-Y. Targeting transcriptional regulators for treatment of anaplastic thyroid cancer. J Cancer Metastasis Treat. 2021;7:27–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Carr FE, Tai PW, Barnum MS, Gillis NE, Evans KG, Taber TH, et al. Thyroid hormone receptor-β (TRβ) mediates runt-related transcription factor 2 (Runx2) expression in thyroid cancer cells: a novel signaling pathway in thyroid cancer. Endocrinology. 2016;157:3278–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ravi N, Yang M, Mylona N, Wennerberg J, Paulsson K. Global RNA expression and DNA methylation patterns in primary anaplastic thyroid cancer. Cancers. 2020;12:680–91.

    Article  CAS  PubMed Central  Google Scholar 

  37. Guigon C, Kim D, Willingham M, Cheng S. Mutation of thyroid hormone receptor-β in mice predisposes to the development of mammary tumors. Oncogene. 2011;30:3381–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Furumoto H, Ying H, Chandramouli G, Zhao L, Walker RL, Meltzer PS, et al. An unliganded thyroid hormone β receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis. Mol Cell Biol. 2005;25:124–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim WG, Zhao L, Kim DW, Willingham MC, Cheng S-Y. Inhibition of tumorigenesis by the thyroid hormone receptor β in xenograft models. Thyroid. 2014;24:260–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. López-Mateo I, Alonso-Merino E, Suarez-Cabrera C, Park JW, Cheng S-Y, Alemany S, et al. Thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells. Thyroid. 2020;30:116–32.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Jerzak KJ, Cockburn JG, Dhesy-Thind SK, Pond GR, Pritchard KI, Nofech-Mozes S, et al. Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study. Breast cancer Res Treat. 2018;171:709–17.

    Article  CAS  PubMed  Google Scholar 

  42. Marlow LA, D’Innocenzi J, Zhang Y, Rohl SD, Cooper SJ, Sebo T, et al. Detailed molecular fingerprinting of four new anaplastic thyroid carcinoma cell lines and their use for verification of RhoB as a molecular therapeutic target. J Clin Endocrinol Metab. 2010;95:5338–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Enomoto K, Zhu X, Park S, Zhao L, Zhu YJ, Willingham MC, et al. Targeting MYC as a therapeutic intervention for anaplastic thyroid cancer. J Clin Endocrinol Metab. 2017;102:2268–80.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lee WK, Kim WG, Fozzatti L, Park S, Zhao L, Willingham MC, et al. Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer. Endocr-Relat cancer. 2020;27:209–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee WK, Lee J, Kim H, Lee SG, Choi SH, Jeong S, et al. Peripheral location and infiltrative margin predict invasive features of papillary thyroid microcarcinoma. Eur J Endocrinol. 2019;181:139–49.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs. Zachary Rae, Michael Kelly, and Kimia Dadkhah for carrying out single-cell RNA sequencing at the Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory (Leidos Biomed), NCI. We also thank Joelle Mornini, NIH Library, for manuscript editing assistance.

Funding

This research is supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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Conception and designs were performed by SC and WKL; Development of methodology and acquisition of data were carried out by WKL, XZ, SP, LZ, and JZ; Analysis and interpretation of data were performed by WKL, XZ, SP, JZ, PM, and SC; Writing, review, and/or revision were performed by SC and WKL. Administrative, technical, or material support were performed by LZ, PM, and SC.

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Correspondence to Sheue-yann Cheng.

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Lee, W.K., Zhu, X., Park, S. et al. Regulation of cancer stem cell activity by thyroid hormone receptor β. Oncogene 41, 2315–2325 (2022). https://doi.org/10.1038/s41388-022-02242-9

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