Molecular Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.

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The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma

International Journal of Molecular Sciences ◽

10.3390/ijms222212216 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12216

Author(s):

Valeria Ramundo ◽

Giada Zanirato ◽

Elisabetta Aldieri

Keyword(s):

Oxidative Stress ◽

Malignant Pleural Mesothelioma ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Asbestos Exposure ◽

Transforming Growth Factor Β ◽

Pleural Mesothelioma ◽

Mesenchymal Transition ◽

Pharmacological Approach

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.

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Epithelial-to-mesenchymal transition, cell polarity and stemness-associated features in malignant pleural mesothelioma

Cancer Letters ◽

10.1016/j.canlet.2011.01.009 ◽

2011 ◽

Vol 302 (2) ◽

pp. 136-143 ◽

Cited By ~ 22

Author(s):

Claudia Casarsa ◽

Niccolò Bassani ◽

Federico Ambrogi ◽

Giuliano Zabucchi ◽

Patrizia Boracchi ◽

...

Keyword(s):

Cell Polarity ◽

Malignant Pleural Mesothelioma ◽

Epithelial To Mesenchymal Transition ◽

Pleural Mesothelioma ◽

Mesenchymal Transition

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Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.333 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 333-333

Author(s):

Iris Simon ◽

Paul Roepman ◽

Andreas Schlicker ◽

Josep Tabernero ◽

Ian Majewski ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Mismatch Repair ◽

Mutation Frequency ◽

Epithelial To Mesenchymal Transition ◽

Molecular Classification ◽

Chemotherapy Response ◽

Intrinsic Subtypes ◽

Mesenchymal Transition

333 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans. For colorectal cancer (CRC), however, a molecular classification is still missing. Methods: Using gene expression data of 188 stage I-IV colorectal cancer (CRC) patients, a molecular subtype classification was developed. The classifier was validated in 543 stage II and III patients and the subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular marker status and chemotherapy response. Results: CRC is a heterogeneous disease that consists of at least three major intrinsic subtypes (A-, B-, C-type). The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A-type and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Conclusions: We have developed a diagnostic single sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and consequently require different treatment strategies. [Table: see text]

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Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity

International Journal of Molecular Sciences ◽

10.3390/ijms20092177 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2177 ◽

Cited By ~ 3

Author(s):

Fernanda Cristina Sulla Lupinacci ◽

Hellen Kuasne ◽

Martin Roffé ◽

Julia Avian Vassalakis ◽

Fernanda Ferreira da Silva ◽

...

Keyword(s):

Translational Control ◽

Tumor Heterogeneity ◽

Epithelial To Mesenchymal Transition ◽

Molecular Classification ◽

High Grade ◽

Translation Rate ◽

Mesenchymal Transition ◽

Expression Of Genes ◽

Polysome Profiling

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.

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Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

Genome Medicine ◽

10.1186/s13073-021-00931-w ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Clément Meiller ◽

François Montagne ◽

Theo Z. Hirsch ◽

Stefano Caruso ◽

Julien de Wolf ◽

...

Keyword(s):

Tumor Microenvironment ◽

Malignant Pleural Mesothelioma ◽

Tumor Heterogeneity ◽

Immunological Synapse ◽

Side Wall ◽

Molecular Classification ◽

Suppressor Gene ◽

Pleural Mesothelioma ◽

Sequencing Analysis ◽

Methylome Analysis

Abstract Background Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

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Aminopeptidase N/CD13 as a potential therapeutic target in malignant pleural mesothelioma

European Respiratory Journal ◽

10.1183/13993003.01610-2017 ◽

2018 ◽

Vol 51 (5) ◽

pp. 1701610 ◽

Cited By ~ 4

Author(s):

Takahiko Otsuki ◽

Taku Nakashima ◽

Hironobu Hamada ◽

Yusuke Takayama ◽

Shin Akita ◽

...

Keyword(s):

Monoclonal Antibody ◽

Malignant Pleural Mesothelioma ◽

Poor Prognosis ◽

Tumour Growth ◽

Tumour Progression ◽

Molecular Target ◽

Aminopeptidase N ◽

Pleural Mesothelioma ◽

Tumour Angiogenesis ◽

Potential Therapeutic Target

Angiogenesis is a crucial factor in the progression of malignant pleural mesothelioma (MPM) and antiangiogenic strategies might be effective against MPM. Aminopeptidase N (APN)/CD13 promotes tumour angiogenesis and is associated with poor prognosis; however, its clinical significance in MPM remains unclear.In 37 consecutive patients with surgically resected MPM, we evaluated the association between immunohistochemical APN/CD13 expression in resected tumours and survival. Additionally, the antitumour and antiangiogenic effects of MT95-4, a fully humanised anti-APN/CD13 monoclonal antibody, were evaluated in mice orthotopically implanted with EHMES-10 (abundantly expressing APN/CD13) and MSTO-211H (scarcely expressing APN/CD13) MPM cells.High tumour APN/CD13 expression was associated with poor prognosis in MPM patients (p=0.04), and MT95-4 treatment reduced tumour growth and angiogenesis in mice harbouring EHMES-10 but not MSTO-211H cells. Furthermore, in mice harbouring EHMES-10 cells, MT95-4 combined with cisplatin more effectively suppressed tumour progression than cisplatin alone.Taken together, these results suggest that APN/CD13 is implicated in the aggressiveness of MPM. Here, MT95-4 treatment reduced tumour progression likely by inhibiting angiogenesis, suggesting APN/CD13 as a potential molecular target for MPM treatment. Additionally, combination treatment with MT95-4 and cisplatin could represent a promising approach to treating MPM exhibiting high APN/CD13 expression.

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Treatment of malignant pleural mesothelioma: current status and future directions

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2010.302 ◽

2016 ◽

Vol 73 (2) ◽

Author(s):

X. Dhalluin ◽

A. Scherpereel

Keyword(s):

Malignant Pleural Mesothelioma ◽

European Society ◽

Poor Prognosis ◽

Asbestos Exposure ◽

Therapeutic Strategies ◽

Current Status ◽

Pleural Mesothelioma ◽

European Respiratory Society ◽

Future Directions ◽

Cell Therapies

Previously considered to be rare, malignant pleural mesothelioma (MPM) is a highly aggressive tumour that has become a very important issue over recent years due to its poor prognosis and its increasing incidence mostly linked to previous asbestos exposure. An optimal treatment for MPM is not established yet; new therapies and predictive tools are still needed in the management of this cancer. Thus the aim of this review is to provide clinicians clear and up-to-dated data on the latest therapeutic strategies for MPM patients in 2010. The guidelines recently proposed by the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) taskforce are summarized here. The authors also briefly reviewed the future directions in MPM treatment including targeted therapies, gene or cell therapies.

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A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability

Cancers ◽

10.3390/cancers12071863 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1863

Author(s):

Mauricio P. Pinto ◽

Miguel Córdova-Delgado ◽

Ignacio N. Retamal ◽

Matías Muñoz-Medel ◽

M. Loreto Bravo ◽

...

Keyword(s):

Gastric Cancer ◽

Latin American ◽

Epithelial To Mesenchymal Transition ◽

Low Cost ◽

Molecular Classification ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Barr Virus ◽

Clinical Applicability ◽

Stratification System

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic

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