Preclinical Mouse Models of Thyroid Cancer

Division Of Basic Sciences - Nci

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Abstract

Our present study provides compelling evidence to show that TRbeta acts as a tumor suppressor by regulating CSC activity. TRbeta functions as a potent inhibitor of CSC activity by blocking tumor-sphere formation in vitro and by reducing CSCs and their self-renewal capacity in vivo to block tumor initiation and progression. The inhibition of CSC activity by TRbeta is mediated by suppressing key stem-cell regulators, including ALDHs, KLF2, ABCG2, SOX2, beta-catenin, and CD44. T3, in particular, potentiates the CSC-suppressing activity of TRbeta, suggesting that TRbeta directly regulates transcription of CSC-related genes. Remarkably, our single-cell transcriptomic analysis of tumors induced by ATC patient-derived cells showed that TRbeta significantly reduces total CSC population size, blocks recruitment of mesenchymal stem cells (MSCs) into the tumor microenvironment, and ultimately shifts the cell landscape toward a tumor-free milieu through re-differentiation. This CSC-suppressing action of TRbeta has clinical significance. Our integrative transcriptome analysis of The Cancer Genome Atlas (TCGA) reveals inverse relationships of the THRB gene with many essential CSC-related genes in diverse human cancers, including thyroid, breast, glioma, kidney, and lung cancer. These observations provide additional evidence to support our findings that TRbeta can function to suppress CSC activity. Furthermore, the THRB gene expression was suppressed in these cancers but not in normal tissues, supporting the premise that TRbeta is a tumor suppressor. In breast cancer, the expression of the THRB gene is downregulated during progression to triple-negative breast cancer (TNBC), as occurs in anaplastic changes in ATC. Further, the low THRB expression significantly contributes to poor clinical outcomes, including advanced tumor stage and shorter disease-free/overall survival of the patients through cMYC signaling activation and transcriptional/metabolic hyperactivity, which are hallmarks of CSCs. Our studies have shown that TRbeta could be tested as a potential molecular target for therapeutic intervention of ATC.