Upregulation of mesothelial genes in ovarian carcinoma cells is associated with an unfavorable clinical outcome and the promotion of cancer cell adhesion.
Apoptosis
/ genetics
Ascites
/ genetics
Biomarkers, Tumor
/ metabolism
Cell Adhesion
Cell Line, Tumor
Cystadenocarcinoma, Serous
/ genetics
Disease-Free Survival
Epithelium
/ pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Neoplasm Grading
Neoplasm Proteins
/ genetics
Ovarian Neoplasms
/ genetics
Peritoneal Neoplasms
/ secondary
Polymorphism, Single Nucleotide
/ genetics
Spheroids, Cellular
/ pathology
Treatment Outcome
Up-Regulation
/ genetics
adhesion
calretinin
driver mutations
mesothelial cells
metastasis
ovarian cancer
podoplanin
transcriptomics
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
19
03
2020
revised:
19
05
2020
accepted:
25
05
2020
pubmed:
14
6
2020
medline:
7
7
2021
entrez:
14
6
2020
Statut:
ppublish
Résumé
A hallmark of ovarian high-grade serous carcinoma (HGSC) is its early and massive peritoneal dissemination via the peritoneal fluid. It is generally believed that tumor cells must breach the mesothelium of peritoneal organs to adhere to the underlying extracellular matrix (ECM) and initiate metastatic growth. However, the molecular mechanisms underlying these processes are only partially understood. Here, we have analyzed 52 matched samples of spheroids and solid tumor masses (suspected primary lesions and metastases) from 10 patients by targeted sequencing of 21 loci previously proposed as targets of HGSC driver mutations. This analysis revealed very similar patterns of genetic alterations in all samples. One exception was FAT3 with a strong enrichment of mutations in metastases compared with presumed primary lesions in two cases. FAT3 is a putative tumor suppressor gene that codes for an atypical cadherin, pointing a potential role in peritoneal dissemination in a subgroup of HGSC patients. By contrast, transcriptome data revealed clear and consistent differences between tumor cell spheroids from ascites and metastatic lesions, which were mirrored by the in vitro adherence of ascites-derived spheroids. The adhesion-induced transcriptional alterations in metastases and adherent cells resembled epithelial-mesenchymal transition, but surprisingly also included the upregulation of a specific subset of mesothelial genes, such as calretinin (CALB2) and podoplanin (PDPN). Consistent with this finding, calretinin staining was also observed in subsets of tumor cells in HGSC metastases, particularly at the invasive tumor edges. Intriguingly, a high expression of either CALB2 or PDPN was strongly associated with a poor clinical outcome. siRNA-mediated CALB2 silencing triggered the detachment of adherent HGSC cells in vitro and inhibited the adhesion of detached HGSC cells to collagen type I. Our data suggest that the acquisition of a mesenchymal-mesothelial phenotype contributes to cancer cell adhesion to the ECM of peritoneal organs and HGSC progression.
Identifiants
pubmed: 32533757
doi: 10.1002/1878-0261.12749
pmc: PMC7463315
doi:
Substances chimiques
Biomarkers, Tumor
0
Neoplasm Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2142-2162Informations de copyright
© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
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