Endocrine Abstracts

Undifferentiated thyroid carcinomas are extremely aggressive and currently lack effective treatment. Aberrant RAS-ERK signaling, triggered mainly by BRAF and RAS mutations, is responsible for the occurrence and progression of most thyroid carcinomas, which led to the clinical use of small kinase inhibitors targeting kinases of the pathway. The results were disappointing, because of the emergence of resistance and high-associated toxicity. A more specific approach, targeting signaling regulators, could circumvent those problems. IQGAPs are scaffold proteins considered hubs of signaling, that have been associated with other human carcinomas and could represent excellent therapeutic targets. In this work, we are interested in defining IQGAPs involvement in thyroid carcinomas, taking into account the main oncogenic drivers, BRAF and RAS. We interrogated public databases to examine IQGAPs expression and their association with clinicopathological features in human thyroid carcinomas. IQGAPs loss- and gain-of-function clones were generated, using cell lines derived from human anaplastic thyroid carcinomas, to analyze IQGAPs involvement in signaling, transcriptional regulation by RNA sequencing and tumor-related processes using different functional assays. A chick-embryo model was employed to explore the participation of IQGAPs in thyroid tumorigenesis in vivo. The results show that IQGAP1 expression is high in human thyroid tumors, especially in those with BRAF mutations, and is associated with aggressive tumor features. The opposite occurs with IQGAP2, suggesting a tumor suppressor role. IQGAP1 silencing and IQGAP2 overexpression affected tumor-related cellular processes, and the outcome depends on the driver mutation. The underlying mechanism is not straightforward, as several signaling pathways were disturbed. Importantly, IQGAP1 silencing and IQGAP2 overexpression, while not prevented ERK phosphorylation, blocked the phosphorylation of Ribosomal S6 Kinase (RSK), a key cytoplasmic ERK effector. RNAseq analysis suggested the acquisition of partial mesenchymal phenotypes, and extracellular matrix regulation, upon IQGAP1 and 2 silencing. In vivo experiments indicate that IQGAP1 is not involved in the growth of the primary tumor, but it is required for intravasation and metastatic dissemination. Our data suggest that IQGAPs pro- or anti-tumorigenic abilities depend on the oncogenic driver, and that modulate tumor cellular processes, at least in part through RSK, leading to a reduction of metastatic dissemination.