Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins - Research findings

Sep 21, 2026

The study investigates how gene regulatory networks (GRNs) that emerged during metazoan evolution become disrupted in cancer. It focuses on an imbalance in co-expression between unicellular-origin (UC) and multicellular-origin (MC) genes. Using gene co-expression analysis and protein sequence conservation to classify UC and MC origins, the work examines RNA-seq data across 31 tumor types and corresponding normal tissues. Results show that the strongest tumor–normal differences occur in mixed UC-MC modules, with increasing rewiring linked to tumor grade and stage, and enrichment for somatic mutations and copy-number amplifications in cancer genes. The findings implicate breakdown and rewiring of metazoan GRNs in cancer development and progression.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages25

Reading Time1 h 3 min

AccessFree to download

Abstract

Background

Results

Conclusions

Background

Evolution of metazoan GRNs and co-expression balance

Cancer hallmarks and the atavism hypothesis

Trigos et al. Genome Biology (2024) 25:110 [https://doi.org/10.1186/s13059-024-03247-1](https://doi.org/10.1186/s13059-024-03247-1) Genome Biology RESEARCH Open Access Disruption of metazoan gene regulatory networks in cancer alters the balance of co-expression between genes of unicellular and multicellular origins Anna S. Trigos 1,2,3*, Felicia Bongiovanni1,2, Yangyi Zhang1,2, Maia Zethoven1,2, Richard Tothill4, Richard Pearson1,2,3,5, Anthony T. Papenfuss 1,2,6 and David L. Goode 1,2* *Correspondence: [anna.trigos@petermac.org](anna.trigos@petermac.org); david. [goode@petermac.org](goode@petermac.org) 1 Peter MacCallum Cancer Centre, 305 Grattan St., Melbourne, VIC 3000, Australia 2 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia 3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia 4 Centre for Cancer Research, The University of Melbourne, Parkville, VIC 3010, Australia 5 Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC 3010, Australia 6 Bioinformatics Division, The Walter & Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia Abstract Background: Metazoans inherited genes from unicellular ancestors that perform essential biological processes such as cell division, metabolism, and protein translation. Multicellularity requires careful control and coordination of these unicellular genes to maintain tissue integrity and homeostasis. Gene regulatory networks (GRNs) that arose during metazoan evolution are frequently altered in cancer, resulting in overexpression of unicellular genes. We propose that an imbalance in co-expression of unicellular (UC) and multicellular (MC) genes is a driving force in cancer. Results: We combine gene co-expression analysis to infer changes to GRNs in cancer with protein sequence conservation data to distinguish genes with UC and MC origins. Co-expression networks created using RNA sequencing data from 31 tumor types and normal tissue samples are divided into modules enriched for UC genes, MC genes, or mixed UC-MC modules. The greatest differences between tumor and normal tissue co-expression networks occur within mixed UC-MC modules. MC and UC genes not commonly co-expressed in normal tissues form distinct co-expression modules seen only in tumors. The degree of rewiring of genes within mixed UC-MC modules increases with tumor grade and stage. Mixed UC-MC modules are enriched for somatic mutations in cancer genes, particularly amplifications, suggesting an important driver of the rewiring observed in tumors is copy number changes. Conclusions: Our study shows the greatest changes to gene co-expression patterns during tumor progression occur between genes of MC and UC origins, implicating the breakdown and rewiring of metazoan gene regulatory networks in cancer development and progression. Keywords: Cancer, Gene expression, Expression modules, Atavism, Evolution © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://](http://)[ ](http://)[creativecommons.org/licenses/by/4.0/](creativecommons.org/licenses/by/4.0/. The Creative Comm

FAQs

What imbalance does the study propose as a driver of cancer?

The study proposes that an imbalance in co-expression between unicellular-origin (UC) and multicellular-origin (MC) genes drives cancer-related changes in gene regulation.

How are UC and MC genes distinguished in the analysis?

UC and MC genes are distinguished by combining gene co-expression analysis with protein sequence conservation data that indicates genes’ evolutionary origins.

Where do tumor versus normal differences in co-expression networks appear most strongly?

The largest differences occur within mixed UC-MC modules, where MC and UC genes that are not commonly co-expressed in normal tissues form distinct co-expression modules in tumors.

Sep 21, 2026

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