Integrative multi-omics analysis of intratumoral and intertumoral heterogeneity in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a deadly pleural malignancy with over 90% mortality within five years and a median survival of approximately 7 months without treatment. The current first-line chemotherapy, a combination of pemetrexed and cisplatin, modestly extends survival, with the addition of bevacizumab offering a further 2-month benefit. Radiation therapy, while not effective as a primary treatment due to the extensive field required, plays a role in multimodal approaches or as localized therapy. The diversity in patient outcomes and responses to treatments indicates significant tumor heterogeneity in MPM, underscoring the need for therapies that consider this variability and target the molecular specifics of individual MPM cases. Tumor heterogeneity is observed at both intertumor and intratumor levels, encompassing tumor cells and their microenvironments. Molecular profiling studies have further highlighted this heterogeneity, complicating the identification of a unique biomarker for MPM. Overall design: To address these challenges and improve clinical outcomes, an enhanced understanding of MPM's biological heterogeneity is crucial. This can inform prognostic assessments and the development of precise therapeutic strategies, including immunotherapy and targeted therapy. Our approach to dissecting MPM heterogeneity involves comprehensive testing using whole exome sequencing (WES), total RNA sequencing, mass cytometry, and mass spectrometry on tissue samples collected from three distinct sites during macroscopic complete resection. This multi-faceted analysis promises to deepen our understanding of MPM and pave the way for more personalized treatment modalities.