Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer
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Abstract
Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in epithelial malignancies with focus on colon cancer. By taking advantage of the coexistence of subpopulations of fully epithelial (EpCAM hi ) and quasi-mesenchymal and highly metastatic (EpCAM lo ) cells in conventional human cancer cell lines, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1 alters the AS pattern of a broad spectrum of targets including CD44 and NUMB , thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and clinical validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival in colon cancer. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in epithelial cancers, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.
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Elevated AKT3 and KIT, reduced mitochondrial respiratory complex I activity, and modified alternative splicing landscape are biological hallmarks of CMS4.
“Among other biological hallmarks of this subtype shown to contribute to CMS4 traits feature elevated AKT3 (42) and KIT (43), reduced mitochondrial respiratory complex I activity (44)—possibly resulting from KIT overexpression (43)—or modified alternative splicing landscape (45).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [45]
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- Authors
- Xu, T., Verhagen, M., Joosten, R., Sun, W., Sacchetti, A., Munoz Sagredo, L., Orian-Rousseau, V., & Fodde, R.
- Affiliations
- Erasmus MC (NL)
- Génétique et biologie du développement (FR)
- Institute of Biological and Chemical Systems - Functional Molecular Systems (IBCS FMS), Karlsruhe Institute of Technology
- Corresponding author
- Fodde, Riccardo
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-11-08
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9674345
- OpenAlex
- W4308554062
- Cited by
- 25
- References
- 63
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 8 · 2023: 3
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- China Scholarship Council (201806300047)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- alternative splicing, epithelial-mesenchymal transition, phenotypic plasticity, colon cancer, ZEB1, ESRP1, RNA-binding proteins, CD44, Numb, metastasis, tumor invasion, EpCAM, splicing isoforms, prognostic factors
- MeSH terms
- Epithelial Cell Adhesion Molecule, Adaptation, Physiological, Colonic Neoplasms, Humans, RNA Splicing, Alternative Splicing
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