Deep dive to the immune response against murine mesothelioma delineates a roadmap for preclinical investigations to advance anti-mesothelioma immune therapeutics
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE197542 | GEO | 2022/12/22
REPOSITORIES: GEO
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Project description: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.
2022-01-14 | E-MTAB-9727 | biostudies-arrayexpress
Project description:Malignant mesothelioma (MM) is an asbestos-related malignancy. MM cells have a broad histological spectrum, and consist mainly of epithelioid, sarcomatoid, and biphasic cell types. The prognosis of MM is generally poor. We applied a copy-number analysis to the identification of new fragile genes in regions 3p21 and 16p13.3 in MM.
2016-11-13 | GSE57464 | GEO
Project description:Malignant mesothelioma (MM) is an asbestos-related malignancy. Discrimination between MM and reactive mesothelial hyperplasia (RM) is often difficult. MM cells have a broad histological spectrum, and consist mainly of epithelioid, sarcomatoid, and biphasic cell types. The prognosis of MM is generally poor, but better prognosis has been reported with the epithelioid type of MM than the non-epithelioid type. We applied a genome-wide analysis to the identification of new markers that may aid in differentiating the epithelioid type of MM from other histological types and from RM cells. Array-based comparative genomic hybridization analysis was performed on malignant mesothelioma (MM) primary cell cultures, reactive mesothelial hyperplasia (RM) primary cell cultures; early passage of in vitro primary cell cultures to minimize acquisition of additional genomic changes. If available, matched peripheral blood was applied to analysis.
2014-11-22 | E-GEOD-52788 | biostudies-arrayexpress
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Project description:The goal of this study was to identify transcriptome alterations behind the antitumor effect of PEGASEMP, a liposomal formulation of doxorubicin targeted by the nucleolin-binding F3 peptide, and hence infer on the mechanism of action. It was used microarray technology to assess the gene expression alterations upon treatment of a human biphasic mesothelioma orthotopic mouse model (aggressive disease subtype) with PEGASEMP.
2021-02-16 | GSE121205 | GEO
Project description:Malignant mesothelioma (MM) is an asbestos-related malignancy. Discrimination between MM and reactive mesothelial hyperplasia (RM) is often difficult. MM cells have a broad histological spectrum, and consist mainly of epithelioid, sarcomatoid, and biphasic cell types. The prognosis of MM is generally poor, but better prognosis has been reported with the epithelioid type of MM than the non-epithelioid type. We applied a genome-wide analysis to the identification of new markers that may aid in differentiating the epithelioid type of MM from other histological types and from RM cells.
2014-11-22 | GSE52788 | GEO
Project description:Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma
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Project description:Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, resulting in pain and shortness of breath. We compared mesothelioma cell lines that were injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumours displayed a transcriptional signature consistent with increased activity of nuclear receptorsPPARα and PPARγ and with an increased abundance of endogenous PPAR-activating ligands. We found that chemical probe GW6471 is a potent dual PPARα/γ antagonist with anti-invasive and anti-proliferative activity in vitro. However, administration of GW6471 at doses that provided sustained plasma exposure levels sufficient for inhibition of PPARα/γ transcriptional activity did not result in significant anti-mesothelioma activity in mice. Lastly, we demonstrate that the in vitro antitumour effect of GW6471 is off-target. We conclude that dual PPARα/γ antagonism alone is not a viable treatment modality for mesothelioma.
2021-11-14 | GSE180618 | GEO
Project description:The expression of human microRNAs in the cellular fraction of human peripheral blood of patients with diagnosed malignant mesotheliomas and asbestos-exposed controls. Altered expression of several miRNAs were observed for patients with diagnosed malignant mesotheliomas in comparison with asebstos-expsoed controls. The study group consists of 23 patients with diagnosed malignant mesothelioma (mean age 66 years, range 34 – 84 years). Patients were not treated with chemotherapy or radiation therapy before sample collection. The histological subtypes were: one sarcomatoid, seven biphasic, and twelve epithelioid cases. In three cases the histological subtype was unknown. The control group consists of 17 asbestos-exposed age-matched volunteers without any diagnosed cancer (mean age 68 years, range 47 – 80 years). Oligonucleotide microarrays were purchased from the Norwegican Microarray Consortium (www.microarray.no). The mirVana miRNA Probe Set v2.0 (Ambion) based on the miRBase Sequence Database v8.0. was used.
2012-01-11 | E-GEOD-29707 | biostudies-arrayexpress
Project description:The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and Lats2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in human subcutaneous xenograft models and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the exquisite sensitivity of mesothelioma to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has great potential to treat multiple Hippo-mutant solid tumor types.
2023-10-04 | GSE222962 | GEO