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.

TERT mutations are present but uncommon in mPTCs. Apparently, in mPTCs, the occurrence of TERT mutations is not correlated with unfavorable clinical features.

Epithelial–mesenchymal transition (EMT) is a multistep process that allows epithelial cells to acquire mesenchymal properties. Fundamental in the early stages of embryonic development, this process is aberrantly activated in aggressive cancerous cells to gain motility and invasion capacity, thus promoting metastatic phenotypes. For this reason, EMT is a central topic in cancer research and its regulation by a plethora of mechanisms has been reported. Recently, genomic sequencing and functional genomic studies deepened our knowledge on the fundamental regulatory role of noncoding DNA. A large part of the genome is transcribed in an impressive number of noncoding RNAs. Among these, long noncoding RNAs (lncRNAs) have been reported to control several biological processes affecting gene expression at multiple levels from transcription to protein localization and stability. Up to now, more than 8000 lncRNAs were discovered as selectively expressed in cancer cells. Their elevated number and high expression specificity candidate these molecules as a valuable source of biomarkers and potential therapeutic targets. Rising evidence currently highlights a relevant function of lncRNAs on EMT regulation defining a new layer of involvement of these molecules in cancer biology. In this review we aim to summarize the findings on the role of lncRNAs on EMT regulation and to discuss their prospective potential value as biomarkers and therapeutic targets in cancer.

Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene.

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting.

BackgroundPapillary Thyroid Carcinomas (PTCs) are generally indolent tumors. However, a small but significant percentage of PTCs behaves aggressively, progressing to a diffuse metastatic spreading and leading to patient's death. The lack of reliable markers for predicting the metastatic behavior of these tumors prevents a correct risk based stratification of the disease, thus contributing to the issue of patients’ overtreatment. In this study we aimed at identifying genetic features associated with the development of distant metastasis in PTCs.ResultsWe showed that DM PTCs are characterized by a moderate degree of copy number alterations but display low level of microsatellite instability and a low mutational burden. We identified duplication of Chr1q, duplication of Chr5p harboring the TERT genomic locus and mutations of TERT promoter as distinctive features of DM PTCs. These three genetic variables defined a signature (THYT1) that was significantly associated with a metastatic behavior and a shortened survival. We analyzed the THYT1 signature in PTCs fine needle aspirate biopsies (FNAB) and we demonstrating the applicability of this signature as a molecular marker in the pre-operative diagnostic setting of PTCs.Materials and MethodsA consecutive series of 2,937 thyroid malignancies, diagnosed at the Arcispedale S. Maria Nuova - IRCCS, Italy between 1978 and 2015 were searched to retrieve those who developed distant metastasis (DM, n = 50). We performed a deep profiling to explore the genomic landscape of these tumors.ConclusionsOverall our data identify the first genetic signature that independently predicts metastasis and negative outcome of PTCs, and lay the basis for the possible application of the THYT1 as prognostic marker to improve risk-based stratification and management of PTC patients.

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