Evaluating cell lines as models for metastatic cancer through integrative analysis of open genomic data

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. However, it is still unknown to what extent they adequately resemble the disease in patients. The recent accumulation of large-scale genomic data in cell lines, mouse models, and patient tissue samples provides an unprecedented opportunity to evaluate the suitability of cell lines for metastatic cancer research. In this work, we used breast cancer as a case study. The comprehensive comparison of the genetic profiles of 57 breast cancer cell lines with those of metastatic breast cancer samples revealed substantial genetic differences. In addition, we 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 MDA-MB-231, the most commonly used triple negative cell line for metastatic breast cancer research, had little genomic similarity with Basal-like metastatic breast cancer samples. We further compared cell lines with organoids, a new type of preclinical model which are becoming more popular in recent years. We found that organoids outperformed cell lines in resembling the transcriptome of metastatic breast cancer samples. However, additional differential expression analysis suggested that both types of models could not mimic the effects of tumor microenvironment and meanwhile had their own bias towards modeling specific biological processes. Our work provides a guide of cell line selection in metastasis-related study and sheds light on the potential of organoids in translational research.