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Transcriptional Heterogeneity Underlying Cancer Cell Migration Converges on Shared Regulatory Programs.

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Title: Transcriptional Heterogeneity Underlying Cancer Cell Migration Converges on Shared Regulatory Programs.
Authors: Ortiz I; Department of Bioengineering, Rice University, Houston, TX 77005, USA., Taufalele PV; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Dunagan VL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Hodge SS; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA., Wang J; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Liu Q; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Reinhart-King CA; Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Source: Genes [Genes (Basel)] 2026 Aug 29; Vol. 17 (9). Date of Electronic Publication: 2026 Aug 29.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE
Imprint Name(s): Original Publication: Basel : MDPI
MeSH Terms: Cell Movement*/genetics , Neoplasms*/genetics , Neoplasms*/pathology , Gene Expression Regulation, Neoplastic* , Genetic Heterogeneity*, Transcription Factors/genetics ; Transcription Factors/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Melanoma/genetics ; Melanoma/pathology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Humans ; Cell Line, Tumor ; TEA Domain Transcription Factors ; Female
Abstract: Background/Objectives: Cancer cell migration is a hallmark of cancer and is associated with metastasis. While large-scale functional screens have identified regulators of migration, less is known about how intrinsic transcriptional heterogeneity drives highly migratory phenotypes within individual cancer models or whether these transcriptional changes are conserved across different models of varying tissues of origin. This study aims to define shared and cell line-specific transcriptional programs associated with cancer cell migration and analyze their relevance to patient datasets. Methods: Five cancer cell lines across three cancer types (breast, colorectal, and melanoma) were subjected to transwell-based migratory sorting to isolate highly and weakly migratory subpopulations. Bulk RNA sequencing, differential gene expression analysis, Gene Ontology (GO) enrichment, and upstream regulator prediction were performed. Public tumor datasets were analyzed to evaluate gene expression and its association with patient survival. Results: EVA1A was consistently upregulated in all highly migratory (HM) subpopulations. Multiple GO terms were enriched across all cell lines, often driven by distinct gene signatures, indicating convergence at the level of biological processes despite transcriptional divergence. TEAD4 was predicted as an upstream regulator, and increased TEAD4 nuclear localization was observed in four of the five HM subpopulations. EVA1A and TEAD4 expression were elevated in tumors relative to normal tissues, with cancer type-dependent survival outcomes. Conclusions: Migratory selection was accompanied by extensive transcriptional change within each model, yet across five models spanning three tissue types these changes converged on shared biological processes rather than shared genes. Migration-associated phenotypes may therefore be better defined by pathway-level than single-gene analyses, and the clinical relevance of regulatory nodes such as TEAD4 appears conditional on cancer type.
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Grant Information: na W.M. Keck Foundation; 1842494 U.S. National Science Foundation
Contributed Indexing: Keywords: RNA sequencing; TEAD4; cancer cell heterogeneity; cancer cell migration
Substance Nomenclature: 0 (Transcription Factors)
0 (TEA Domain Transcription Factors)
0 (DNA-Binding Proteins)
0 (Muscle Proteins)
0 (TEAD4 protein, human)
Entry Date(s): Date Created: 20260926 Date Completed: 20260926 Latest Revision: 20260929
Update Code: 20260929
PubMed Central ID: PMC13606308
DOI: 10.3390/genes17091042
PMID: 42792937
Database: MEDLINE
Description
ISSN:2073-4425
DOI:10.3390/genes17091042