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Cell-to-cell adhesion is a key element in epithelial tissue integrity and homeostasis during embryogenesis, response to damage, and differentiation. Loss of cell adhesion and gain of mesenchymal features, a phenomenon known as epithelial to mesenchymal transition (EMT), are essential steps in cancer progression. Interestingly, downregulation or degradation by endocytosis of epithelial adhesion molecules (e.g., E-cadherin) associates with EMT and promotes cell migration. Autophagy is a physiological intracellular degradation and recycling process. In cancer, it is thought to exert a tumor suppressive role in the early phases of cell transformation but, once cells have gained a fully transformed phenotype, autophagy may fuel malignant progression by promoting EMT and conferring drug resistance. In this review, we discuss the crosstalk between autophagy, EMT, and turnover of epithelial cell adhesion molecules, with particular attention to E-cadherin.

Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.

Inactivation of p53 contributes significantly to the dismal prognosis of breast tumors, most notably triple-negative breast cancers (TNBCs). How the relief from p53 tumor suppressive functions results in tumor cell aggressive behavior is only partially elucidated. In an attempt to shed light on the implication of microRNAs in this context, we discovered a new signaling axis involving p53, miR-30a and ZEB2. By an in silico approach we identified miR-30a as a putative p53 target and observed that in breast tumors reduced miR-30a expression correlated with p53 inactivation, lymph node positivity and poor prognosis. We demonstrate that p53 binds the MIR30A promoter and induces the transcription of both miRNA strands 5p and 3p. Both miR-30a-5p and -3p showed the capacity of targeting ZEB2, a transcription factor involved in epithelial–mesenchymal transition (EMT), tumor cell migration and drug resistance. Intriguingly, we found that p53 does restrain ZEB2 expression via miR-30a. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and distal spreading and impinges upon miR-200c expression. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds support to the notion that miRNAs represent key elements of the complex network whereby p53 inactivation affects TNBC clinical behavior.

This paper presents FpClass, a prediction method for physical protein-protein interactions. The method is benchmarked against experimental data and is used to predict, among others, partners of interactome 'orphans'. Protein-protein interactions (PPIs) are useful for understanding signaling cascades, predicting protein function, associating proteins with disease and fathoming drug mechanism of action. Currently, only ∼10% of human PPIs may be known, and about one-third of human proteins have no known interactions. We introduce FpClass, a data mining–based method for proteome-wide PPI prediction. At an estimated false discovery rate of 60%, we predicted 250,498 PPIs among 10,531 human proteins; 10,647 PPIs involved 1,089 proteins without known interactions. We experimentally tested 233 high- and medium-confidence predictions and validated 137 interactions, including seven novel putative interactors of the tumor suppressor p53. Compared to previous PPI prediction methods, FpClass achieved better agreement with experimentally detected PPIs. We provide an online database of annotated PPI predictions ( http://ophid.utoronto.ca/fpclass/ ) and the prediction software ( http://www.cs.utoronto.ca/~juris/data/fpclass/ ).

Extraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma. In this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285. Between June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18–30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% [95% CI 1–36]) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine [35%] of 26 patients), increased concentration of alanine aminotransferase (six [23%]), and increased aspartate aminotransferase (five [19%]). Pazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients. Spanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.

The contribution of MEF2 TFs to the tumorigenic process is still mysterious. Here we clarify that MEF2 can support both pro-oncogenic or tumor suppressive activities depending on the interaction with co-activators or co-repressors partners. Through these interactions MEF2 supervise histone modifications associated with gene activation/repression, such as H3K4 methylation and H3K27 acetylation. Critical switches for the generation of a MEF2 repressive environment are class IIa HDACs. In leiomyosarcomas (LMS), this two-faced trait of MEF2 is relevant for tumor aggressiveness. Class IIa HDACs are overexpressed in 22% of LMS, where high levels of MEF2, HDAC4 and HDAC9 inversely correlate with overall survival. The knock out of HDAC9 suppresses the transformed phenotype of LMS cells, by restoring the transcriptional proficiency of some MEF2-target loci. HDAC9 coordinates also the demethylation of H3K4me3 at the promoters of MEF2-target genes. Moreover, we show that class IIa HDACs do not bind all the regulative elements bound by MEF2. Hence, in a cell MEF2-target genes actively transcribed and strongly repressed can coexist. However, these repressed MEF2-targets are poised in terms of chromatin signature. Overall our results candidate class IIa HDACs and HDAC9 in particular, as druggable targets for a therapeutic intervention in LMS.

Background Cancer resistance is one of the major challenges in oncology, often resulting in disease relapse and poor patient outcomes. Within the RNA family, microRNAs (miRNAs) regulate core biological processes and have been recognized also as critical contributors of tumor resistance and therapy failure. Being pivotal, they are increasingly exploited as biomarkers in various settings. Although in silico analyses facilitate miRNAs identification, PCR-based approaches remain essential to validate their expression. Currently, a plethora of well-established, single-target methods exist but multiplex detection from the same input have been only rarely explored. Methods We present miRquad, the first-in-class digital PCR (dPCR) TaqMan™ multiplex clinical research assay for miRNA detection in head and neck (HNC) cancers. Based on a patented prognostic signature including miR-21-5p, miR-96-5p, miR-21-3p and miR-429, the assay would enable simultaneous miRNA analysis via qPCR and dPCR on multiple clinically relevant sample types. Results We designed and optimized miRquad using both synthetic controls and retrospective patient-derived tissues, sera and saliva. A multicentre ring study was conducted to evaluate assay reliability across different platforms, demonstrating strong correlation with commercial singleplexes, broad applicability, reduced turnaround time (TAT) and cost-effectiveness. Finally, we provide evidence for its potential clinical application to predict disease outcome in HNC, testing miRquad on tumoral and peritumoral tissues, sera and saliva samples collected throughout patient follow up. Conclusions The assay overcomes common challenges associated with multiple miRNAs detection, particularly in liquid biopsy samples (e.g., multiple pipetting issues, increased consumption of sample for multiple assessment, extended TAT for complete profiling) and provides robust and accurate detection, demonstrating potential for real-time patient monitoring and prognostication in HNC.

Autophagy is an intracellular catabolic process that is increasingly being recognized as a crucial factor in several human diseases including cancers. Mounting evidence suggests that autophagy allows tumor cells to overcome otherwise fatal stresses and to increase dissemination. Nevertheless, how autophagy controls these processes and in particular how it impinges on cell-cell adhesion is still poorly understood. Here, we investigate the role of autophagy in the turnover of the epithelial adhesion molecule E-cadherin in the context of breast cancer. We demonstrated in breast cancer cell lines that autophagy impinges on E-cadherin expression and in the configuration of adherens junctions. Besides, we showed that E-cadherin colocalizes with LC3B and SQSTM1/p62, two components of the autophagosome machinery. Pull down and immunoprecipitation analyses provided evidence that E-cadherin and SQSTM1/p62 physically interact. Moreover, the physical closeness of E-cadherin and SQSTM1/p62 was demonstrated by proximity ligation assays in breast cancer cell lines and primary tumors. Finally, we proved that the silencing of SQSTM1/p62 diminished the E-cadherin/LC3B colocalization, further supporting the role of SQSTM1/p62 in E-cadherin delivery to autophagosomes. These findings suggest that the activation of autophagy, reported in breast cancers with poor prognosis and in dormant breast cancer cells, may contribute to the control of tumor progression via downmodulation of E-cadherin protein levels.

Background The Complexity INdex in SARComas (CINSARC) is a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity. This study aims to assess CINSARC value of in an independent series of high‐risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG‐STS 1001). Patients and Methods Patients with available pre‐treatment samples, treated with 3 cycles of either standard (ST) preoperative or histotype‐tailored (HT) chemotherapy, were scored according to CINSARC (low‐risk, C1; high‐risk, C2). The 10‐year overall survival probability (pr‐OS) according to SARCULATOR was calculated, and patients were classified accordingly (low‐risk, Sarc‐LR, 10‐year pr‐OS>60%; high‐risk, Sarc‐HR, 10‐year pr‐OS<60%). Survival functions were estimated using the Kaplan–Meier method and compared using log‐rank test. Results Eighty‐six patients were included, 30 C1 and 56 C2, 49 Sarc‐LR and 37 Sarc‐HR. A low level of agreement between CINSARC and SARCULATOR was observed (Cohen's Kappa = 0.174). The 5‐year relapse‐free survival in C1 and C2 were 0.57 and 0.55 (p = 0.481); 5‐year metastases‐free survival 0.63 and 0.64 (p = 0.740); 5‐year OS 0.80 and 0.72 (p = 0.460). The 5‐year OS in C1 treated with ST and HT chemotherapy was 0.84 and 0.76 (p = 0.251) respectively; in C2 treated it was 0.72 and 0.70 (p = 0.349). The 5‐year OS in Sarc‐LR treated with S and HT chemotherapy was 0.80 and 0.82 (p = 0.502) respectively; in Sarc‐HR it was 0.70 and 0.61 (p = 0.233). Conclusions Our results, although constrained by the small size of the series, suggest that CINSARC has weak prognostic power in high‐risk, localized STS treated with neoadjuvant chemotherapy. This study aims to assess the value of CINSARC, a transcriptional signature derived from the expression of 67 genes involved in mitosis control and chromosome integrity, in an independent series of high‐risk patients with localized soft tissue sarcoma (STS) treated with preoperative chemotherapy within a prospective, randomized, phase III study (ISG‐STS 1001). As it can be seen in the figure, which shows Kaplan Meier curves for relapse‐free survival, metastases‐free survival, and overall survival in CINSARC low‐risk (C1) and high‐risk (C2) patients, our results, although constrained by the small size of the series, suggest that CINSARC has a weak prognostic power in this population.

Imatinib is the first-line treatment for advanced gastrointestinal stromal tumors (GISTs) harboring KIT or PDGFRA mutations. Unfortunately, resistance invariably develops, typically through secondary KIT / PDGFRA mutations. Here, we describe an unprecedented case of acquired imatinib resistance associated with an oncogenic driver switch, from a KIT mutation to an NTRK3 fusion. The index case was a KIT exon 11-mutated gastric GIST that progressed on imatinib. Despite retaining the original KIT mutation and DOG1 expression, the relapsed tumor lost KIT expression and exhibited a dedifferentiated phenotype. Transcriptomic profiling revealed a de novo EML4::NTRK3 gene fusion. In vitro modeling demonstrated that EML4::NTRK3 confers imatinib resistance, while sensitizing GIST cells to NTRK inhibitors. This first reported instance of an NTRK fusion as a secondary event in GIST progression underscores the importance of testing for NTRK alterations in tumors that have developed resistance to tyrosine kinase inhibitors to ensure patients are offered all available therapeutic options.