Prognostic Value of EMT Gene Signature in Malignant Mesothelioma

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.

Omics Overview of the SPARC Gene in Mesothelioma

“…Higher expression of SPARC gene is associated with poorer overall survival (Log rank p = 3.6 × 10 −5 ) and disease-free survival (Log rank p = 0.023) in the MESO cohort (Figure 1D,E) and in pancancer (Figure 1F,G). The prognostic value of the EMT gene signature in MESO has been demonstrated elsewhere and by our group [24].…”

Characterization of KLHL14 anti-oncogenic action in malignant mesothelioma

“…Significantly, KLHL14 has been identified as a potential regulator of epithelial-mesenchymal transition (EMT) in amniotic epithelial stem cells, a cellular model where this process occurs spontaneously [ 16 ]. Notably, EMT is a hallmark of tumorigenic process and is involved in the metastatic process for the majority of solid tumors, including MM [ [17] , [18] , [19] ].…”