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

Abstract

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.

Ancestral gene regulatory networks drive cancer

“…Although increased expression of UC genes seems to be a general phenomenon, specific up-regulation depends on the function of the associated processes, suggesting One prediction from this theory is that cancer will overexpress genes and processes with a UC origin, while simultaneously underexpressing the MC pathways that promote cellular cooperation for the good of the organism. This prediction is confirmed in the analysis of Trigos et al (9). that cancer atavism is not a haphazard affair but an ancient choreography of correlated gene expression.…”

“…Trigos et al (9) studied gene expression in seven types of solid tumors and investigated the corresponding gene ages using a method known as phylostratigraphy (10,11). Specifically, the authors (9) assigned genes to one of 16 phylostrata and then compared gene expression in tumors with that in normal tissue.…”

“…Almost half of the correlations (11 of 24) were associated with cell death. Trigos et al (9) hypothesize that the disruption of cross-talk between older (UC) and younger (MC) processes may prove to be a key factor in the onset of tumorigenesis.…”

“…Applying DAVID to the total list of 103 genes (12 discussed in the main paper of ref. 9 and 91 in the Supporting Information), reveals significant enrichment in ribosomal biogenesis, urea cycle regulation, RNA catabolic pathways, and glycolysis. Also highly enriched are the so-called 14-3-3 proteins, which lie downstream of Rap1 and serve to modulate the effect of many receptor tyrosine kinase signaling cascades, including those that activate MEK and PI3K.…”

“…The analysis presented by Trigos et al (9) offers the opportunity to identify the links between the UC processes involved in this response and the MC processes that regulate it, allowing the design of therapeutic regimens that take advantage of the difference in the rates of evolution between tumors and the surrounding microenvironment.…”