Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy.

The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFß target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.

A novel BRAF mutation in association with primary amelanotic melanoma with oral metastases.

BACKGROUND: In the context of amelanotic melanoma, little is known on the genetic or molecular background that determines the onset of this peculiar phenotype of melanoma and its sites of metastatic spread. However, it appears that amelanotic melanomas frequently lack BRAF mutations. OBJECTIVE: To report the genetical analysis of one case amelanotic melanoma developing oral metastasis. METHODS: The BRAF mutational status of the primary lesion was assessed by both Sanger sequencing and pyrosequencing. RESULTS: Both methodologies showed changes in three nucleotides: C1796T; G1798A and T1799A. These mutations should result in a rare double aminoacid substitution in codons 599 and 600 of the BRAF protein (BRAF T599I/V600K). CONCLUSION: This unusual mutation was associated with an uncommon clinical phenotype of the primary tumour and with an unusual site of metastatic spread. In the lack of comparable data, a potential association between the unusual mutation and clinical findings remains a matter of further studies.