Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy

Abstract

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 TGFβ 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.

Proteomic identification of proteins differentially expressed following overexpression of hTERT (human telomerase reverse transcriptase) in cancer cells

“…It is well known that hTERT promotes EMT and during EMT there is change in expression of some epithelial and mesenchymal markers; level of mesenchymal markers goes up while that of epithelial markers goes down. CDH6 which is a type 2 cadherin and an epithelial marker drives EMT during embryonic development and it is aberrantly re-activated in cancer [36]. We found downregulation of CDH6 in U2OS cells when hTERT is overexpressed showing that hTERT promotes mesenchymal character in these cells.…”

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

“…The diverging results may be ascribed to the different models used; however the link between autophagy and EMT seems to be conceivable. Recently, this connection has been further reinforced by the demonstration that cadherin-6 (Figure 2), a type 2 cadherin that marks cells that undergo EMT and correlates with metastatic ability in papillary thyroid cancers, restrains autophagy, and promotes reorganization of mitochondrial network (135). Autophagy targeting via hydroxychloroquine has now moved into clinical trials and a recent review (136) discusses how inducing or inhibiting autophagy can be achieved in preclinical models.…”

Starvation‐induced autophagy promotes the invasion and migration of human bladder cancer cells via TGF‐β1/Smad3‐mediated epithelial‐mesenchymal transition activation

“…16 Autophagy plays an important role in the invasion and migration of many types of tumor cells. 22 However, autophagy can also inhibit the invasion and migration of glioblastoma cells, 23 papillary thyroid carcinoma cells, 24 and colon cancer cells. 21 Sphingosine kinase 1 (SPHK1) can promote the invasion and migration of hepatocellular carcinoma through TNF receptor-associated factor 2 (TRAF2)-mediated autophagy activation, and the F I G U R E 4 Starvation-induced autophagy promotes EMT through the TGF-β/Smad signaling pathway.…”