Emerging Genes in Thyroid Cancer

The focus of our research is the study of the main molecular steps that lead to the transformation of a normal thyroid follicular cell into an invasive thyroid. Thyroid differentiation stems from the presence of iodide-metabolizing genes required for the biosynthesis of thyroid hormones, and are essential for the beneficial radioiodide treatment of thyroid tumors. However, some tumors progress to metastatic disease refractory to radioiodine due to loss of differentiation. In the era of cancer genomics, how genetic alterations and impaired pathways connect with the loss of thyroid differentiation and metastasis formation is a hot topic in the field that remains elusive. Altered genes include mutations in BRAF, RAS and RET/PTC leading to the aberrant activation of the MAPK signaling pathway, driving progression through a dedifferentiation process. However, although significant, these advances have not enabled yet the translation to the clinic of curative therapies or reliable diagnostic markers. It is now becoming increasingly clear that this loss of differentiation is a multifactorial process in which a multiplicity of mechanisms is responsible for the impairment of iodide-metabolizing genes resulting in a limited dose delivery to the tumor and decreased radiosensitivity. Our main objective is to identify new diagnostic and therapeutic targets for metastatic thyroid cancer by studying in a holistic, integrative and technically innovative manner a variety of new mechanisms underlying the loss of differentiation and metastatic progression. Based on a comprehensive and multidimensional sequencing analysis in both primary tumors and serums of a cohort of thyroid cancer patients, we have already unveiled some promising molecules and mechanisms. Among them, we study the role played by: (i) ADAR1, a protein involved in A-to-I editing of RNA, a widespread post-transcriptional process that has recently emerged as an important mechanism in cancer biology. (ii) SIX1, an oncogenic transcription factor that enhances TGFβ oncogenic action; (iii) IQGAP1 and 2, two scaffold proteins that serve as dimerization platforms in which ERK dimers are assembled. (iv) TAZ/YAP mediators of the Hippo pathway that have been involved in cancer resistant to kinase inhibitors. (v) Analysis of regulatory circuits formed by important post-transcriptional actors, such as microRNAs and long non-coding RNAs, to control the expression of iodide-metabolizing genes. (vi) Identification of circulating exosomes specific of thyroid cancer metastasis. In our work, we use different experimental approaches that range from an orthotopic mouse model -which mimics the formation of human metastatic thyroid cancer-, a panel of cell lines with the main genetic alterations of these tumors and massive sequencing analysis. The results are extended to the clinic by analyzing potential biomarkers and targets in independent cohorts of patients with metastatic thyroid cancer.  These studies are providing important insights into the molecular mechanisms of metastatic thyroid cancer, ultimately leading to the identification of novel targets for diagnostic and therapeutic interventions.