Identification of an onco domain at the C-terminal region of TRbeta1. Compelling evidence from our in vitro and in vivo studies has shown that TRbetaPV functions as an oncogene. A fundamental question is whether the oncogenic activity of mutated TRbeta1 is uniquely dependent on the PV mutated sequence. Using four C-terminal frame-shift mutants- TRbetaPV, Mkar, Mdbs, and AM-we examined that region in the oncogenic actions of TRbeta1 mutants. TRbetaPV, Mkar, and Mdbs were identified in RTH patients and have frameshift mutations in helix 11-12 of TRbeta1. AM is a mutant that was constructed to contain only the upstream 11 amino acids of Mkar. Remarkably, these C-terminal mutants induced similar growth of tumors in mouse xenograft models. Molecular analyses showed that they physically interacted with the p85alpha regulatory subunit of PI3K similarly in cells. An in vitro GST-binding assay showed that they bound to the C-terminal Src-homology 2 (CSH2) of p85alpha with markedly high avidity. The sustained association of mutants with p85alpha led to activation of the common PI3K-AKT-ERK/STAT3 signaling to promote cell proliferation and invasion and to inhibit apoptosis. Thus, these results argue against the oncogenic activity of TRbetaPV being uniquely dependent on the PV mutated sequence. Rather, these four mutants favor a C-terminal conformation that could interact with the CSH2 domain of p85alpha to initiate activation of PI3K to relay downstream signaling to promote tumorigenesis. This study uncovered a novel onco-domain at the mutated C-terminal region of TRbeta1. Diet-induced obesity increases tumor growth and promotes anaplastic change in thyroid cancer via activation of JAK2-STAT3 signaling In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity rates. Large population studies suggest that increasing body mass index is tightly linked to advanced thyroid cancer risks. However, the underlying molecular mechanisms by which obesity could contribute to thyroid cancer progression remained unclear. In line with epidemiologic findings in human cancer, treatment of ThrbPV/PVPten+/- mice with a high fat diet (HFD-ThrbPV/PVPten+/- mice) led to exacerbated tumor phenotypes with decreased survival, increased tumor growth, development of anaplasia, tumor cell invasion, and metastasis. Elevated serum leptin levels (5-fold) secreted by enlarged adipocytes in HFD-treated mice led to the activation of leptin receptor-JAK2-STAT3 signaling to drive aggressive cancer progression. Thus, our study provided the direct evidence that diet-induced obesity exacerbates thyroid cancer progression. Our studies have uncovered one underlying molecular mechanism to understand how a high fat diet could contribute to thyroid cancer progression. Importantly, our results suggest that STAT3 could be a potential therapeutic target for obesity-induced thyroid cancer [This possibility is being tested in our ongoing studies. Synergistic signaling of KRAS and TRbeta mutants promotes undifferentiated thyroid cancer via up-regulation of MYC and activated Integrin-ERBB2 signaling Aiming to develop a mouse model to understand dedifferentiated thyroid cancer, we genetically targeted the KrasG12D mutation to thyroid epithelial cells of ThrbPV/PV mice. ThrbPV/PVKrasG12D mice exhibited poorer survival, larger tumor size, and more frequent occurrences of distant metastases than ThrbPV/PV mice do. Significantly, ThrbPV/PVKrasG12D mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology. Within the anaplastic foci, the thyroid specific transcription factor Paired box gene 8 (PAX8) expression was virtually lost, accompanied by concomitant up-regulation of MYC. Up-regulated MYC contributes to the initiation of undifferentiated thyroid cancer, in part, via enhancing TRbetaPV-mediated repression of the Pax8 expression. cDNA microarray analyses comparing global gene expression profiles of thyroid cells of KrasG12D mice and thyroid tumor lesions of ThrbPV/PV and ThrbPV/PVKrasG12D mice identified 14 upstream regulators, functioning as key effectors in growth factor-induced signaling to promote thyroid tumor growth of ThrbPV/PVKrasG12D mice. Further analysis identified integrins as key upstream regulators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of ThrbPV/PVKrasG12D mice. Our studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRbetaPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer.