Ricardo Coelho

Frequency of TERT promoter mutations in human cancers

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

A family-network model for wealth distribution in societies

A model based on first-degree family relations network is used to describe the wealth distribution in societies. The network structure is not a priori introduced in the model, it is generated in parallel with the wealth values through simple and realistic dynamical rules. The model has two main parameters, governing the wealth exchange in the network. Choosing their values realistically, leads to wealth distributions in good agreement with measured data. The cumulative wealth distribution function has an exponential behavior in the low and medium wealth limit, and shows the Pareto-like power-law tail for the upper 5% of the society. The obtained Pareto indexes are in good agreement with the measured ones. The generated family networks also converge to a statistically stable topology with a simple Poissonian degree distribution. On this family network many interesting correlations are studied, and the main factors leading to wealth diversification and the formation of the Pareto law are identified.

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for Monocarboxylate Transporters as metabolic targets for therapy.

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia‐inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors.

Peritoneal dissemination of ovarian cancer: role of MUC16-mesothelin interaction and implications for treatment

ABSTRACT Introduction: Peritoneal dissemination is a particular form of malignant progression in ovarian cancer, preceding hematogenic or lymphatic dissemination. Thus, prevention of peritoneal implantation of cancer cells is envisioned to inhibit neoplastic dissemination and therefore prolong disease remission and patient’s survival. Areas covered: An extended review on the role of MUC16 (CA125) and mesothelin (MSLN), expressed in a high percentage of ovarian carcinomas, indicate that this duet is relevant for the contact between cancer cells and mesothelial cells in homotypic (cancer cell-cancer cell) and heterotypic (cancer cell-mesothelial cell) interactions. This review discusses the reasons underlying the clinical failure of immunotherapeutic strategies targeting MUC16. Clinical data on MSLN targeting agents such as antibody-based immunotoxins or antibody drug conjugates are also reviewed. The promising anti-tumor effect of CAR-T cells directed to MUC16 or MSLN is emphasized. New emerging strategies specifically disrupting the MUC16-MSLN interaction are at the forefront of this review, including TRAIL ligands bound to MSLN targeting MUC16 expressing cells and single chain monoclonal antibodies and immunoadhesins recognizing MSLN-MUC16 binding domains. Expert commentary: Based on existing evidences the authors advocate that agents targeting MUC16-MSLN may add to the therapeutic armamentarium directed to abrogate peritoneal homing of ovarian cancer.

Telomerase and N-Cadherin Differential Importance in Adrenocortical Cancers and Adenomas†

Adrenocortical carcinomas (ACC) are most frequently highly aggressive tumors. We assessed the telomerase reverse transcriptase (TERT) and N‐cadherin role in the biology of ACC and their potential utility as molecular biomarkers, in different types of tumoral adrenocortical tissue. A total of 48 adrenal cortex samples (39 tumoral and 9 normal adrenal glands) were studied. TERT promoter mutations were searched by PCR and Sanger sequencing in two hotspots positions (−124 and −146). Also, telomerase and N‐cadherin expression were evaluated by immunohistochemistry. TERT promoter mutations were not detected in any of the samples either malignant or benign. Telomerase nuclear expression was present in 26.6% of ACC and in 45.5% of non‐functioning adenomas. It was absent in benign Cushings lesions and in normal adrenal glands. Contrarily, N‐cadherin was always expressed in the cellular membranes of benign adenomas or normal adrenals but no expression was detected in the majority of ACC. Nuclear telomerase and membrane N‐cadherin expression were positively correlated in ACCs. We conclude that in ACC, the loss of N‐cadherin is a frequent phenomenon while the existence of TERT promoter mutations is not and nuclear telomerase expression is present in only a minority of cases. Since the loss of N‐cadherin expression was identified in both high and low proliferative ACC, this marker should be considered important for diagnostic application. Our study also suggests the existence of a TERT non‐canonical function in cell adhesion. J. Cell. Biochem. 118: 2064–2071, 2017.

Mucins and Truncated O-Glycans Unveil Phenotypic Discrepancies between Serous Ovarian Cancer Cell Lines and Primary Tumours

Optimal research results rely on the selection of cellular models capable of recapitulating the characteristics of primary tumours from which they originate. The expression of mucins (MUC16 and MUC1) and truncated O-glycans (Tn, STn and T) represents a characteristic footprint of serous ovarian carcinomas (SOCs). Therefore, selecting ovarian cancer (OVCA) cell lines that reflect this phenotype is crucial to explore the putative biological role of these biomarkers in the SOC setting. Here, we investigated a panel of OVCA cell lines commonly used as SOC models, and tested whether, when cultured in 2D and 3D conditions, these recapitulate the mucin and O-glycan expression profiles of SOCs. We further explored the role of truncating the O-glycosylation capacity in OVCAR3 cells through knockout of the COSMC chaperone, using in vitro and in vivo assays. We found that the majority of OVCA cell lines of serous origin do not share the mucin and truncated O-glycan footprint of SOCs, although 3D cultures showed a higher resemblance. We also found that genetic truncation of the O-glycosylation capacity of OVCAR3 cells did not enhance oncogenic features either in vitro or in vivo. This study underscores the importance of well-characterized cellular models to study specific features of ovarian cancer.