Molecular Mechanisms of Tumor Progression and Novel Therapeutic and Diagnostic Strategies in Mesothelioma

Abstract

Mesothelioma is characterized by the inactivation of tumor suppressor genes, with frequent mutations in neurofibromin 2 (NF2), BRCA1-associated protein 1 (BAP1), and cyclin-dependent kinase inhibitor 2A (CDKN2A). These mutations lead to disruptions in the Hippo signaling pathway and histone methylation, thereby promoting tumor growth. NF2 mutations result in Merlin deficiency, leading to uncontrolled cell proliferation, whereas BAP1 mutations impair chromatin remodeling and hinder DNA damage repair. Emerging molecular targets in mesothelioma include mesothelin (MSLN), oxytocin receptor (OXTR), protein arginine methyltransferase (PRMT5), and carbohydrate sulfotransferase 4 (CHST4). MSLN-based therapies, such as antibody-drug conjugates and immunotoxins, have shown efficacy in clinical trials. OXTR, upregulated in mesothelioma, is correlated with poor prognosis and represents a novel therapeutic target. PRMT5 inhibition is being explored in tumors with MTAP deletions, commonly co-occurring with CDKN2A loss. CHST4 expression is associated with improved prognosis, potentially influencing tumor immunity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown promise in some cases; however, resistance mechanisms remain a challenge. Advances in multi-omics approaches have improved our understanding of mesothelioma pathogenesis. Future research will aim to identify novel therapeutic targets and personalized treatment strategies, particularly in the context of epigenetic therapy and combination immunotherapy.

Keywords: BAP1; CHST4; FAK; Hippo signaling pathway; OXTR; immune checkpoint inhibitors; mesothelioma.

Figure 1

A schematic illustration depicting the dysregulation of the NF2/Merlin-Hippo signaling cascade in mesothelioma cells. Extracellular signals are transmitted through cell–cell interactions (via cadherins), cell–matrix interactions (via integrins), and growth factor receptors, such as receptor tyrosine kinases, influencing the tumor-suppressive function of Merlin. When Merlin is in an active, underphosphorylated state, it modulates the Hippo signaling cascade and inhibits the activity of YAP1/TAZ transcriptional coactivators. However, in mesothelioma cells, frequent alterations in Merlin (the NF2 gene product) and key Hippo signaling pathway components, including LATS1/2, lead to YAP1/TAZ activation (underphosphorylation). This, in turn, promotes the expression of multiple pro-oncogenic genes.

Figure 2

Transcriptional regulation machinery comprising BAP1, PRC1, and PRC2. BAP1 is a major deubiquitinase that removes H2AK119Ub, a histone marker deposited by the PRC1 complex. BAP1 loss leads to H2AK119Ub accumulation, which in turn promotes recruitment of the PRC2 complex including EZH2, resulting in elevated H3K27me3 levels and transcriptional repression.

Figure 3

The CDKN2A gene produces two distinct tumor suppressor proteins through alternative reading frames, namely, p16INK4A (P16), derived from the alpha transcript, and p14ARF (P14), derived from the beta transcript. These proteins play pivotal roles in halting cell cycle progression, particularly during the G1 to S phase transition.

Figure 4

Role of CHST4 in lymphocyte homing and mesothelioma. Lymphocytes begin their interaction with high endothelial venules by binding L-selectin to its ligand, leading to integrin-mediated adhesion and transendothelial migration. Sulfation by CHST4 plays a pivotal role in the enhancement of lymphocyte homing and the chemokine-induced activation step of this sequential adhesion process. In mesothelioma, CHST4 mRNA expression exhibited a substantial correlation with immune–gene signatures representing tumor-infiltrating lymphocytes. CHST4 is hypothesized to contribute to tumor immunity against mesothelioma via lymphocyte infiltration.