Autophagy and epithelial to mesenchymal transition (EMT) are major biological processes in cancer. Autophagy is a catabolic pathway that aids cancer cells to overcome intracellular or environmental stress, including nutrient deprivation, hypoxia and drugs effect. EMT is a complex transdifferentiation through which cancer cells acquire mesenchymal features, including motility and metastatic potential. Recent observations indicate that these two processes are linked in a complex relationship. On the one side, cells that underwent EMT require autophagy activation to survive during the metastatic spreading. On the other side, autophagy, acting as oncosuppressive signal, tends to inhibit the early phases of metastasization, contrasting the activation of the EMT mainly by selectively destabilizing crucial mediators of this process. Currently, still limited information is available regarding the molecular hubs at the interplay between autophagy and EMT. However, a growing number of evidence points to the functional interaction between cytoskeleton and mitochondria as one of the crucial regulatory center at the crossroad between these two biological processes. Cytoskeleton and mitochondria are linked in a tight functional relationship. Controlling mitochondria dynamics, the cytoskeleton cooperates to dictate mitochondria availability for the cell. Vice versa, the number and structure of mitochondria, which are primarily affected by autophagy-related processes, define the energy supply that cancer cells use to reorganize the cytoskeleton and to sustain cell movement during EMT. In this review, we aim to revise the evidence on the functional crosstalk between autophagy and EMT in cancer and to summarize the data supporting a parallel regulation of these two processes through shared signaling pathways. Furthermore, we intend to highlight the relevance of cytoskeleton and mitochondria in mediating the interaction between autophagy and EMT in cancer.

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.

The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box binding transcription repressors which include Snail (SNAI) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin modifying proteins including lysine specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background. We show here that either treatment blocked Slug-dependent repression of the E-cadherin promoter and inhibited the motility and invasion of tumor cell lines without any effect on their proliferation. These effects correlated with induction of epithelial and repression of mesenchymal markers and were phenocopied by LSD1 or Slug down-regulation. Parnate treatment also inhibited bone marrow homing/engraftment of Slug-expressing K562 cells. Together, these studies support the concept that targeting Snail/Slug-dependent transcription repression complexes may lead to the development of novel drugs selectively inhibiting the invasive potential of cancer cells.