Multiomic assessments of LNCaP and derived cell strains reveal determinants of prostate cancer pathobiology

A cornerstone of research to improve cancer outcomes involves studies of model systems to identify causal drivers of oncogenesis, understand mechanisms leading to metastases, and develop new therapeutics. Although most cancer types are represented by large cell line panels that reflect diverse neoplastic genotypes and phenotypes found in patients, prostate cancer is notable for a very limited repertoire of models that recapitulate the pathobiology of human disease. Of these, the lymph node carcinoma of the prostate (LNCaP) cell line has served as the major resource for basic and translational studies. Here, we delineated the molecular composition of LNCaP and multiple substrains through analyses of whole-genome sequences, transcriptomes, chromatin structure, androgen receptor (AR) cistromes, and functional studies. Our results determined that LNCaP exhibits substantial subclonal diversity, ongoing genomic instability, and phenotype plasticity. Several oncogenic features were consistently present across strains, but others were unexpectedly variable, such as ETV1 expression, Y chromosome loss, a reliance on WNT and glucocorticoid receptor activity, and distinct AR alterations maintaining AR pathway activation. These results document the inherent molecular heterogeneity and ongoing genomic instability that drive diverse prostate cancer phenotypes and provide a foundation for the accurate interpretation and reproduction of research findings.