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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
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An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype
Irina M Shapiro1, Albert W Cheng, Nicholas C Flytzanis
1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Plos Genetics
|August 31, 2011
Summary
Alternative splicing significantly impacts epithelial-mesenchymal transition (EMT), a key process in cancer. This study identified an EMT splicing signature, revealing its role in cell phenotype changes and potential as a diagnostic marker for breast cancer progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Epithelial-mesenchymal transition (EMT) is crucial for embryonic development and cancer progression.
- While transcriptional regulation of EMT is well-studied, the role of alternative splicing remains less understood.
- Comprehensive analysis of splicing changes during EMT is needed to understand its contribution to morphological alterations.
Purpose of the Study:
- To identify and characterize the alternative splicing signature associated with EMT.
- To investigate the regulatory mechanisms and functional consequences of EMT-associated alternative splicing.
- To explore the potential of EMT splicing patterns as diagnostic and prognostic markers in breast cancer.
Main Methods:
- Utilized an established cell culture model for EMT induction.
- Performed RNA-sequencing (RNA-Seq) analyses to identify alternative splicing events.
- Validated EMT splicing signatures in human breast cancer cell lines and primary tumor samples.
Main Results:
- Identified a distinct alternative splicing signature for EMT, enriched in genes involved in cell phenotype changes (cytoskeleton, cell junctions, migration).
- Found that EMT-associated splicing events are regulated by splicing factors like RBFOX, MBNL, CELF, hnRNP, and ESRP.
- Demonstrated that EMT splicing patterns can classify breast cancer subtypes (basal and luminal) and are present in primary tumors.
- Showed that manipulating splicing factors (ESRP1, RBFOX2) can alter cell morphology and motility, indicating splicing's functional significance in EMT.
Conclusions:
- Alternative splicing plays a significant role in driving phenotypic changes during EMT.
- The identified EMT splicing signature is conserved across cell lines and primary tumors, offering potential for diagnostic and prognostic applications in breast cancer.
- Splicing regulation alone can influence critical aspects of EMT-associated cellular changes.
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