Non-Coding Transcript Heterogeneity in Mesothelioma: Insights from Asbestos-Exposed Mice

Felley‐Bosco, Emanuela; Rehrauer, Hubert

doi:10.3390/ijms19041163

Cited by 8 publications

(6 citation statements)

References 67 publications

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“…Human epithelioid mesothelioma show upregulated expression of coelomic epithelium-associated genes, including of WT1 (Bozzi et al, 2016; de Reyniès et al, 2014). Notably, the non-coding RNA Fendrr ( Fetal-lethal noncoding ) is strongly upregulated in mouse and human epithelioid mesothelioma and shares a bidirectional promoter with the LPM transcription factor gene FOXF1 (Bueno et al, 2016; Felley-Bosco and Rehrauer, 2018; Grote et al, 2013). These observations indicate that at least some populations of mesothelioma cells feature a gene expression profile reminiscent of late developmental markers for the coelomic epithelium.…”

Section: Discussionmentioning

confidence: 99%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

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Section: Discussionmentioning

confidence: 99%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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“…The mechanisms for epigenetic regulation in MPM were principally studied in the context of BAP1 inactivation; they highlighted the role of polycomb repressive complex 2 (PRC2) and histone methyltransferase (28). Other studies also emphasized the involvement of non-coding RNA such as micro-RNA (miRNA) or long non-coding RNA (lncRNA), both of which are deregulated in MPM, in carcinogenesis (29)(30)(31).…”

Section: Molecular Alterationsmentioning

confidence: 99%

The Biology of Malignant Mesothelioma and the Relevance of Preclinical Models

2020

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Malignant mesothelioma (MM), especially its more frequent form, malignant pleural mesothelioma (MPM), is a devastating thoracic cancer with limited therapeutic options. Recently, clinical trials that used immunotherapy strategies have yielded promising results, but the benefits are restricted to a limited number of patients. To develop new therapeutic strategies and define predictors of treatment response to existing therapy, better knowledge of the cellular and molecular mechanisms of MM tumors and sound preclinical models are needed. This review aims to provide an overview of our present knowledge and issues on both subjects. MM shows a complex pattern of molecular changes, including genetic, chromosomic, and epigenetic alterations. MM is also a heterogeneous cancer. The recently described molecular classifications for MPM could better consider inter-tumor heterogeneity, while histo-molecular gradients are an interesting way to consider both intra-and inter-tumor heterogeneities. Classical preclinical models are based on use of MM cell lines in culture or implanted in rodents, i.e., xenografts in immunosuppressed mice or isografts in syngeneic rodents to assess the anti-tumor immune response. Recent developments are tumoroids, patient-derived xenografts (PDX), xenografts in humanized mice, and genetically modified mice (GEM) that carry mutations identified in human MM tumor cells. Multicellular tumor spheroids are an interesting in vitro model to reduce animal experimentation; they are more accessible than tumoroids. They could be relevant, especially if they are co-cultured with stromal and immune cells to partially reproduce the human microenvironment. Even if preclinical models have allowed for major advances, they show several limitations: (i) the anatomical and biological tumor microenvironments are incompletely reproduced; (ii) the intra-tumor heterogeneity and immunological contexts are not fully reconstructed; and (iii) the inter-tumor heterogeneity is insufficiently considered. Given that these limitations vary according to the models, preclinical models must be carefully selected depending on the objectives of the experiments. New approaches, such as organ-on-a-chip technologies or in silico biological systems, should be explored in MM research. More pertinent cell models, based on our knowledge on mesothelial carcinogenesis and considering MM heterogeneity, need to be developed. These endeavors are mandatory to implement efficient precision medicine for MM.

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“…In fact, their expression may, for example, point to a given cell of origin and commitment to epithelial differentiation phenotype. This was observed in patients’ samples by Felley-Bosco and Rehrauer [ 16 ] for FENDRR , a lncRNA found to be overexpressed in tumors developing in mice after exposure to asbestos fibers, and which also clusters with better outcomes in human mesothelioma patients [ 12 ]. Similarly, Meg3 , another lncRNA found to be overexpressed in tumors developing in mice after exposure to asbestos fibers [ 16 ] is overexpressed in TCGA cluster 1, which was characterized by better overall survival [ 12 ] compared to the other 3 clusters of patients with different transcription profiles.…”

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confidence: 79%