Cadherin 6 regulates Epithelial Mesenchymal Transition by restraining autophagy and controlling metabolism in metastatic thyroid cancer

Gugnoni, Mila (2016) Cadherin 6 regulates Epithelial Mesenchymal Transition by restraining autophagy and controlling metabolism in metastatic thyroid cancer, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare, 30 Ciclo. DOI 10.6092/unibo/amsdottorato/8275.
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The transdifferentiation of epithelial cells toward a mesenchymal phenotype(EMT) is a multi-step process fundamental for tumor cells to leave the primary lesion and colonize ectopic sites. Cadherins are structural proteins that also transduce extracellular signals regulating many cellular pathways but the molecular mechanisms guiding this function is poorly understood. Cadherin-6(CDH6) is a type-2 cadherin which drives EMT during development and is re-expressed in some tumors. In thyroid cancer, CDH6 is a target of TGFβ signaling and a marker of EMT, suggesting a role for this protein in the progression of this tumor. Papillary thyroid carcinomas(PTCs) are mostly indolent lesions, but in the 2-5% of cases metastasize. The identification of molecular markers to distinguish which tumors will behave aggressively, would be strategic to develop specific anticancer approaches. In this work, we assessed the role of CDH6 in the metastatic progression of PTCs and evaluated the transcriptional re-programming following TGFβ signaling. We observed that CDH6 knock-down changes cellular morphology and cell-cell interactions, partially reverting the EMT program. Searching for CDH6 interactors we found GABARAP, BNIP3 and BNIP3L/Nix. Through these interactions, CDH6 restrains autophagy and induces DRP1-mediated mitochondrial fission. CDH6 affects mitochondrial structure but also cell metabolism. Indeed, CDH6-mediated mitochondrial fission is required to provide spared mitochondria for a highly energetic profile, needed for cell motility and invasion. Analysis of CDH6 cytoplasmic LIR domains suggests that other cadherins could associate to autophagic machinery regulating the process. Analysis of CDH6 expression in a cohort of human PTCs showed that CDH6 expression is strongly associated with metastatic behavior and worse disease free survival probability of the patients. CDH6 expression is up-regulated specifically in the cells undergoing EMT and leaving the primary site of the tumor. Finally, we attempted to discover new coding and non-coding regulatory elements mediating TGFβ-induced EMT in thyroid cancer cells.

Tipologia del documento
Tesi di dottorato
Gugnoni, Mila
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Cadherins, Epithelial-Mesenchymal Transition(EMT), Autophagy, Metabolism
Data di discussione
18 Aprile 2016

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