Cross-lineage mesenchymal transition in mesothelioma

Mesothelioma is characterized by extreme cellular plasticity, profound stromal remodeling, and near-universal resistance to therapy. While epithelial-mesenchymal transition (EMT) has long been implicated in disease progression, mesothelioma arises within a uniquely heterogeneous cellular ecosystem in which multiple non-epithelial lineages contribute to mesenchymal states. Here, we introduce cross-lineage mesenchymal transition (XMT) as a unifying framework describing the convergence of epithelial, mesothelial, endothelial, immune, hematopoietic, adipocytic, neural, and stem-like cells toward fibroblast-like, extracellular-matrix-producing phenotypes. Mesothelioma is presented as a conceptual framework for studying convergent mesenchymal programming and XMT-related processes, rather than as a definitively proven example of XMT. XMT is driven by shared signaling axes, including TGF-β, Wnt/β-catenin, Notch, hypoxia, and mechanotransduction pathways that erase lineage identity and reinforce mesenchymal programs. Recurrent mesothelioma-associated genomic alterations, particularly loss of BAP1 and CDKN2A, further potentiate XMT by reshaping chromatin accessibility, cell cycle control, metabolic state, and inflammatory signaling, thereby lowering barriers to lineage plasticity. Integrative bulk and single-cell transcriptomic analyses reveal that XMT-associated gene signatures correlate with stromal enrichment, immunosuppressive myeloid and regulatory T cell infiltration, and poor survival in patients with pleural mesothelioma. XMT underlies mesothelioma desmoplasia, immune evasion, and therapy resistance, and represents a tractable vulnerability for stromal, immune, and plasticity-directed therapeutic strategies. Framing mesothelioma through the lens of XMT provides a unifying biological rationale for stromal evolution and identifies actionable pathways-genetic, epigenetic, and microenvironmental mechanisms that may be targeted to overcome plasticity-driven disease progression. This review highlights specific therapeutic strategies, including stromal-targeted approaches aimed at TGF-β signaling and extracellular matrix remodeling, immune-targeted approaches that address myeloid-driven immunosuppression and inflammatory signaling, and plasticity-directed strategies targeting EMT/stemness programs and cellular state transitions.