Abstract
Metastasis is the most common cause of cancer-related death and, as such, there is an urgent need to discover new therapies to treat metastasized cancers. Cancer cell lines are widely-used models to study cancer biology and test drug candidates, yet it is still unknown to what extent do they adequately resemble the disease in patients. The recent accumulation of large-scale genomic data in cell lines, organoids, mouse models, and patient tissue samples provides an unprecedented opportunity to evaluate the suitability of cancer cell lines as models for metastatic cancer research. Using metastatic breast cancer as a case study, we systematically evaluate their suitability as models for metastatic cancer research. The comprehensive comparison of the genomic profiles of 57 breast cancer cell lines with those of metastatic breast cancer samples revealed substantial genomic differences. We also identified cell lines that more closely resemble different subtypes of metastatic breast cancer. Surprisingly, a combined analysis of mutation, copy number variation and gene expression data suggested that MDAMB231, the most commonly used triple negative cell line, had little genomic similarity with Basal-like metastatic breast cancer samples. In addition to cell lines, we analyzed the RNA-Seq data of patient-derived organoids and found organoids outperformed cell lines in resembling the transcriptome of metastatic breast cancer samples. Finally, we characterized systematic difference between metastatic breast cancer and the in vitro models. Our work both provides a guide of cell line selection in metastasis-related study and sheds light on the large potential of organoids in translational research.