Genomic and Transcriptomic Analysis of Pleural Mesothelioma (MPM) Samples Reveal Crucial Insights for Preclinical Testing

Cell lines are extensively used to study cancer biology. However, the use of highly passaged commercial cell lines has to be questioned, as they do not closely resemble the originating tumor. To understand the reliability of preclinical models for MPM studies, we have performed whole transcriptome and whole exome analysis of fresh frozen MPM tumors and compared them to cell lines generated from these tumors as well as commercial cell lines and a preclinical MPM mouse model. Patient-derived cell lines were generated from digested fresh tumors and whole exome sequencing was performed on DNA isolated from FFPE tumor samples, corresponding patient-derived cell lines and normal tissue. For RNA sequencing libraries were prepared from 18 fresh frozen tumor samples, the corresponding 10 patient-derived cell lines and 7 commercial cell lines. Our results identified alterations in tumor suppressor genes like FBXW7, CDKN2A, CDKN2B and MTAP known to drive MPM tumorigenesis. Patient-derived cell lines correlate to a high degree with their originating tumor. Gene expression involved in multiple pathways like EMT, apoptosis, myogenesis and angiogenesis, are upregulated in tumor samples when compared to patient-derived cell lines, however downregulated in commercial cell lines compared to patient-derived cell lines, indicating significant differences between the two model systems. Our results show, that the genome and transcriptome of tumors correlate to a higher degree with patient-derived cell lines rather than commercial cell lines. These results are of major relevance for the scientific community in regard of using cell lines as an appropriate model, resembling the pathway of interest to avoid miss-leading results.