Insights Into Genomic Drivers, Transcriptomic Heterogeneity, and Therapeutic Vulnerabilities From Novel Mesothelioma Cell Lines
Yani Wu, Fang Cao, Jiayin Dai, Zhenli Yang, Yanli Zhu, Dongmei Lin, Xiaocui Bian, Yuqin LiuABSTRACT
Background
Pleural mesothelioma (PM) is an aggressive cancer with limited therapeutic options and poor prognosis, necessitating comprehensive model systems for mechanistic studies and drug discovery.
Methods
Tumor cells were isolated from malignant pleural effusion of PM patients and subjected to primary culture and continuous passaging. Cell lines were successfully established after more than 40 continuous passages in vitro. Cell identification included morphological analysis, species identification, short tandem repeat (STR) profiling, mycoplasma detection, in vitro proliferation assays, in vivo tumorigenicity testing in NOD/SCID mice, and immunohistochemical characterization. Genomic landscapes and transcriptomic profiling were defined by whole‐exome, whole‐genome sequencing, and RNA‐sequencing.
Results
Three Chinese‐derived pleural mesothelioma cell lines (PUMC‐MESO1, PUMC‐MESO3, and PUMC‐MESO4) were successfully established. All three cell lines exhibited epithelioid morphology with adherent growth patterns. Upon subcutaneous transplantation into NOD/SCID mice, PUMC‐MESO1 and PUMC‐MESO4 demonstrated tumorigenicity, while PUMC‐MESO3 remained non‐tumorigenic after 3 months of observation. Histopathological examination confirmed their mesothelioma origin through positive staining for mesothelial markers including calretinin, WT‐1, and D2‐40. Genomic analysis revealed characteristic PM genomic alterations including mutations in BAP1 , NF2, and TP53 , along with CDKN2A deletions. Transcriptomic analyses revealed heterogeneous molecular features among the three cell lines. Although the PUMC‐MESO cell lines displayed distinct clustering patterns relative to the CCLE mesothelioma cohort, each retained transcriptomic similarities to specific established mesothelioma models. Drug sensitivity assays further demonstrated heterogeneous responses to standard therapeutic agents.
Conclusion
This study reports the establishment and characterization of three novel PM cell lines. These models recapitulate key aspects of PM biology, exhibit diverse therapeutic responses, and provide a valuable new resource for investigating disease mechanisms and advancing precision oncology research.