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Updated: Mar 2, 2026
In Vitro Evaluation of Oncogenic Transformation in Human Mammary Epithelial Cells
Published on: September 24, 2020
Altered interactions between unicellular and multicellular genes drive hallmarks of transformation in a diverse range
Anna S Trigos1,2, Richard B Pearson2,3,4, Anthony T Papenfuss1,2,5
1Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
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.
Insights
Cancer cells reactivate ancient unicellular genes while silencing newer multicellular ones. This evolutionary rewiring, driven by specific genes, underlies common cancer traits and suggests new therapeutic targets.
Area of Science:
- Evolutionary biology
- Genomics
- Cancer research
Background:
- Cancer hallmarks like sustained proliferation and suppressed cell death may arise from disrupted ancient regulatory mechanisms.
- The transition to multicellularity involved conserved gene networks controlling fundamental cellular processes.
Purpose of the Study:
- To investigate the association between the evolutionary age of human genes and their expression patterns in solid tumors.
- To identify key genes and regulatory mechanisms driving common cancer phenotypes based on evolutionary principles.
Main Methods:
- Phylostratigraphy was used to date the evolutionary emergence of human genes.
- Gene expression levels were analyzed using RNA sequencing data from The Cancer Genome Atlas (TCGA) for seven solid cancers.
- Gene regulatory networks were examined to identify highly connected genes mediating unicellular and multicellular function separation.
Main Results:
- Genes conserved with unicellular organisms were significantly upregulated in tumors, while genes of metazoan origin were predominantly inactivated.
- This pattern suggests a coordinated loss of multicellular gene expression and activation of unicellular programs during tumorigenesis.
- Twelve highly connected genes were identified as critical mediators in the separation of unicellular and multicellular functions, acting as potential drivers of cancer.
Conclusions:
- Common cancer phenotypes are linked to the evolutionary history of genes, with altered activity at the interface of unicellular and multicellular gene networks.
- Reactivation of primitive transcriptional programs, driven by evolutionary gene rewiring, contributes to hallmark cancer features.
- Targeting the cross-talk between genes of different evolutionary origins offers a promising, broadly applicable strategy for cancer treatment.
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