Abstract
SummaryAssessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
Highlights
Tumors exhibit a high degree of molecular and cellular heterogeneity due to the impact of genomic aberrations on protein networks underlying physiological cellular activities
We studied a panel of 50 colorectal cancer cell lines using isobaric labeling and tribrid mass spectrometry proteomic analysis in order to assess the impact of somatic genomic variants on protein networks
To assess the reproducibility of our data, we computed the coefficient of variation (CV) (CV = SD/mean) of protein abundances for 11 cell lines measured as biological replicates
Summary
Tumors exhibit a high degree of molecular and cellular heterogeneity due to the impact of genomic aberrations on protein networks underlying physiological cellular activities. We studied a panel of 50 colorectal cancer cell lines (colorectal adenocarcinoma [COREAD]) using isobaric labeling and tribrid mass spectrometry proteomic analysis in order to assess the impact of somatic genomic variants on protein networks. This panel has been extensively characterized by whole-exome sequencing, gene expression profiling, copy number and methylation profiling, and the frequency of molecular alterations is similar to that seen in clinical colorectal cohorts (Iorio et al, 2016). Proteomic and RNA sequencing (RNA-seq) analysis of human induced pluripotent stem cells (iPSCs) engineered with gene knockouts of key
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