A Genome-Wide Systematic Analysis Reveals Different and Predictive Proliferation Expression Signatures of Cancerous vs. Non-Cancerous Cells

Abstract

Understanding cell proliferation mechanisms has been a long-lasting goal of the scientific community and specifically of cancer researchers. Previous genome-scale studies of cancer proliferation determinants have mainly relied on knockdown screens aimed to gauge their effects on cancer growth. This powerful approach has several limitations such as off-target effects, partial knockdown, and masking effects due to functional backups. Here we employ a complementary approach and assign each gene a cancer Proliferation Index (cPI) that quantifies the association between its expression levels and growth rate measurements across 60 cancer cell lines. Reassuringly, genes found essential in cancer gene knockdown screens exhibit significant positive cPI values, while tumor suppressors exhibit significant negative cPI values. Cell cycle, DNA replication, splicing and protein production related processes are positively associated with cancer proliferation, while cellular migration is negatively associated with it – in accordance with the well known “go or grow” dichotomy. A parallel analysis of genes' non-cancerous proliferation indices (nPI) across 224 lymphoblastoid cell lines reveals surprisingly marked differences between cancerous and non-cancerous proliferation. These differences highlight genes in the translation and spliceosome machineries as selective cancer proliferation-associated proteins. A cross species comparison reveals that cancer proliferation resembles that of microorganisms while non-cancerous proliferation does not. Furthermore, combining cancerous and non-cancerous proliferation signatures leads to enhanced prediction of patient outcome and gene essentiality in cancer. Overall, these results point to an inherent difference between cancerous and non-cancerous proliferation determinants, whose understanding may contribute to the future development of novel cancer-specific anti-proliferative drugs.

Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment

“…Although several pioneer studies identified genes periodically expressed during different phases of the cell cycle (4, 5), limited progress has been made regarding the identification of genes with differential expression patterns in tumors with high and low proliferation rates (7,8). Consistent with previous studies using a small number of cancer lines from nine different tumor types (NCI60 set containing 7 colon cancer cell lines; refs.…”

“…Because a major hallmark of cancer is uncontrolled rapid proliferation, it was not surprising to find that many of the genes that control cellcycle progression were deregulated in the different tumor types investigated, compared with the corresponding normal tissue (4,6). However, despite some early studies (7,8), the genes with higher expression in rapidly proliferating tumor cells compared with slowly cycling tumors are not as well characterized. This is of considerable clinical relevance because it has been repeatedly observed that rapid tumor proliferation is associated with poor patient prognosis (9)(10)(11)(12).…”

Predicting Cancer-Specific Vulnerability via Data-Driven Detection of Synthetic Lethality

“…The genes included in the networks are significantly overexpressed both in normal tissues and especially in cancers (Wilcoxon rank sum p values <6.29 3 10 À8 ). Interestingly, the network genes are significantly associated with cancer proliferation and less associated with normal proliferation (Waldman et al, 2013). They are highly enriched with human orthologs of mouse essential genes (hypergeometric p values <1 3 10 À30 ) and are evolutionary conserved (Wilcoxon rank sum p values <2.99 3 10 À17 ).…”

Multiple myeloma cells promote migration of bone marrow mesenchymal stem cells by altering their translation initiation

“…Several studies have highlighted the specific participation of ribosomal proteins, sets of microRNAs, and spliceosomes in translation and concomitant proliferation [47]. Additional research studied the gene signature of 60 cancer cell lines and concluded that protein translation is inseparable from the proliferative phenotype [47]. Topical results summarized the significant role of translational apparatus in cancer promotion and progression [48].…”