Preclinical Mouse Models of Thyroid Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

TRbeta acts as a tumor suppressor by regulating CSC activity. We showed that 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. The present findings have important clinical relevance in developing novel treatment strategy for ATC patients. Our novel findings were published (Doolittle, et al., Oncogene, 2022). 2. Reactivated Thyroid Hormone Receptor beta Attenuates ATC Stem Cell Activity. Our findings shown above prompted us to test the hypothesis that re-activation of the silenced THRB gene could mitigate the CSC activity to block ATA tumor growth. We therefore treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRbeta on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRbeta, as evidenced by western blot and immunohistochemical analyses. The expressed TRbeta inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44 and beta-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation and increasing apoptosis. Our findings indicate that re-expression of the endogenous TRbeta is a novel therapeutic approach for ATC via suppression of CSC activity. These clinically relevant findings have been published (Zhu et al, Endocr Relat Cancer, 2023)