Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity

Abstract

Background and Aims Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses. Methods Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data. Results Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post-transcriptional regulation were recapitulated in cell lines. The five proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared to genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses. Conclusions Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared to genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine.

Molecular characterization of colorectal adenomas reveals POFUT1 as a candidate driver of tumor progression

“…27,28 On RNA and/or protein level, the enrichment of gene sets and pathways were identified to be increasing through different stages of colorectal tumor development, from normal colon, through LRA and HRA to CRC. Comprehensive analysis of high throughput DNA, RNA and protein profiling data of the same samples has not been performed yet for colorectal adenomas, while it did provide additional insights in CRC.…”

“…36 An unexpected result was the overexpression of multiple tumor microenvironment-related genes/proteins in HRAs, including collagens, fibronectin, vimentin, immunoglobulins or calprotectin. 27 In the adenomas, the CAE-driven gene-dosage effect analysis yielded potential drivers of colorectal tumor progression that are already amplified and overexpressed in HRAs-POFUT1, RPRD1B and EIF6. It has been shown that stromal genes can be expressed by epithelial cells, which typically occurs in association with invasion, a phenomenon referred to as epithelial-mesenchymal transition.…”

“…1). 27,28 Gene-dosage effect was also identified for DIS3, which is located on chromosome 13 and often gained in CRC. In the cancers, 92 genes were positively correlated among the data types ( Fig.…”

“…Chromosome 20 was associated with the largest global expression changes on RNA and protein level with 28 genes (~30%), including HNF4A, TOMM34 and RPRD1B, which were previously described to be gained and overexpressed in CRC cell lines and tissues. 27,28 Gene-dosage effect was also identified for DIS3, which is located on chromosome 13 and often gained in CRC. 27,29 Other genomic regions with the highest number of perturbed genes considered almost all chromosomes involved in the CAEs.…”

“…Pairwise correlation analysis was performed between DNA copy number, RNA and protein expression for colorectal adenomas and CRCs. 27,29 Other genomic regions with the highest number of perturbed genes considered almost all chromosomes involved in the CAEs. S6 and Table S8).…”