Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range of solid tumors

Significance Cancer represents a breakdown of molecular mechanisms evolved by multicellular life to impose constraints on cell growth, resulting in more “primitive” proliferative cellular phenotypes. This suggests interpreting the activity of genes in cancer according to their evolutionary origins may provide insights into common mechanisms driving tumorigenesis. We incorporated phylogenetic and interaction data into expression analysis of seven solid tumors, revealing universal strong preferential expression of genes shared with unicellular species in tumors, alongside widespread disruption of links between unicellular and multicellular components of gene regulatory networks. Considering how the constraints imposed on these networks by evolution were altered in tumors identified molecular processes that could be manipulated for therapeutic benefit in cancer and uncovered several promising drug targets. Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.