Prognostic Value of EMT Gene Signature in Malignant Mesothelioma

Our plain-English summary of Prognostic Value of EMT Gene Signature in Malignant Mesothelioma, by L. Wu, K. Yoshihara, H. Yun, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: L. Wu, K. Yoshihara, H. Yun, S. Karim, N. Shokri, F. Zaeimi, H.S.J. Man, A. Zia, E. Felley-Bosco, M. de Perrot
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(5)
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway.

In plain English

This laboratory and computer-based study examined genes linked to epithelial–mesenchymal transition (EMT), a shift of cells from a lining-cell type toward a connective-tissue-like type, in malignant mesothelioma. Building on their earlier mouse work, the authors narrowed a gene list to nine genes associated with survival in the mesothelioma data of The Cancer Genome Atlas (TCGA), a public tumor database. Survival differed significantly by expression of the nine genes (log-rank p = 4.4 × 10^-5). The genes were more highly expressed in non-epithelioid than epithelioid tumors. In 3 pleural effusion samples and 5 tumor biopsies from patients in Toronto, they were expressed mainly in mesothelioma cells. A score built from these genes was associated with overall survival, while a general pan-cancer EMT score did not reach statistical significance. Higher expression of the genes was associated with lower CDKN2A and CDKN2B expression, a weaker interferon response, and higher levels of immune checkpoints such as PD-L1, PD-1 and CTLA4. The study did not measure asbestos exposure in patients. The authors concluded that EMT gene overexpression is an unfavorable prognostic factor for mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory and bioinformatics (multiomic) study. It analyzed public TCGA mesothelioma data with online tools, ran single-cell RNA sequencing on patient samples, and selected genes using an earlier mouse model.
• Who was studied: The mesothelioma (MESO) cohort of The Cancer Genome Atlas (TCGA). Survival figures split it into high and low groups of 43 and 44 patients at median expression. Also studied were samples from untreated patients at University Health Network, Toronto, collected at diagnosis between 2019 and 2020: pleural effusions from 3 patients (all epithelioid) and tumor biopsies from 5 patients (1 biphasic, 4 epithelioid). One patient provided both types of sample.
• Exposure: No asbestos exposure was measured. The study examined the expression of nine EMT genes (COL5A2, ITGAV, SERPINH1, CALD1, TIMP3, SPARC, ACTA2, TNFRSF12A, TPM2). The mouse mesothelioma cell line RN5, used in the earlier gene-selection work, was derived from mice after exposure to asbestos; the fiber type is not named.
• Main results:
  • In the MESO TCGA cohort, survival differed significantly according to expression of the nine EMT genes (log-rank p = 4.4 × 10^-5).
  • In the TCGA data, expression of the nine EMT genes was significantly higher in non-epithelioid than in epithelioid mesothelioma.
  • In single-cell sequencing of the patients' pleural effusion and biopsy samples, the nine genes were overexpressed mainly in mesothelioma cells (cells marked by MSLN expression).
  • The MESO EMT score significantly correlated with overall survival in TCGA, but an EMT score calculated from pan-cancer EMT genes did not reach statistical significance.
  • In TCGA, a high stromal score was associated with worse survival, and MESO EMT scores positively correlated with the stromal score.
  • Expression of the EMT genes was associated with upregulation of immune checkpoints CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1) and TIGIT. It was associated with downregulation of LAG3, LGALS9 and VTCN1.
  • Expression of COL5A2, ITGAV, SERPINH1, CALD1, SPARC and ACTA2 was associated with downregulation of the interferon-alpha and interferon-gamma response.
  • Expression of CDKN2A and CDKN2B negatively correlated with expression of all nine EMT genes. Mutations in the EMT genes themselves were extremely rare.
  • In the TCGA data, low expression of CDKN2A and CDKN2B was associated with worse survival.
• The authors' conclusion: The authors concluded that EMT gene overexpression is an unfavorable prognostic factor for mesothelioma. They also concluded that this gene signature could have a potential role as a prognostic biomarker and could point to potential treatment targets.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Tumor Microenvironment, CDKN2A, PD-L1.

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