Establishment and characterization of 24 breast cancer cell lines and 3 breast cancer organoids reveals molecular heterogeneity and drug response variability in malignant pleural effusion-derived models

Abstract Intratumoral heterogeneity of breast cancer cells causes undesired drug resistance and predispose to disease recurrence. We investigate the molecular heterogeneity of breast cancer cells derived from malignant pleural effusions (MPE) to understand variations in drug resistance and cellular evolution. MPE provides a unique environment, with cells experiencing significant microenvironmental changes that promote intratumoral heterogeneity and therapeutic resistance. By establishing 24 cell lines and 3 organoids from MPE samples of breast cancer patients, we performed extensive genomic, transcriptomic, and drug sensitivity analyses. Our findings reveal substantial genetic and transcriptomic diversity among MPE-derived cell lines, highlighting dynamic alterations in driver mutations and signaling pathways that correlate with variable drug responses. Notably, temporal and spatial heterogeneity within patient-derived samples emphasized the adaptability of breast cancer cells in MPE, as different subclones displayed distinct drug sensitivities. This work underscores the critical role of molecular profiling in understanding treatment resistance in breast cancer, presenting MPE-derived cell lines as valuable preclinical models for exploring personalized therapies in aggressive cancer phenotypes.