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Published on: June 13, 2014
SNAI1 ablation alters integrin-mediated adhesion and endocytic fate
Chrysoula Tsirigoti1,2, Mohamad Moustafa Ali1, Anita Morén1
1Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Abstract:
Transcription factor SNAI1 guides plasticity and invasiveness in cancer. Using a complete SNAI1 knockout in mesenchymal, triple-negative breast cancer cells, unbiased genome-wide transcriptomic analysis revealed a marked under-expression of integrin-based adhesion and endocytic components. Utilizing this knockout cell model, complementary breast cancer cell models and functional screening of multiple differentially expressed genes, we found that the pioneering transcription factor FOXA1, whose expression is repressed by SNAI1, associates with several key mediators of the cellular phenotype. FOXA1 represses the small GTPase ARF6 and its exchange factor PSD4. In addition, some of the integrin and matrix metalloproteinase genes are regulated by the transcriptional FOXA1 signal. Accordingly, SNAI1 knockout cells presented poor adhesion to collagen type I or fibronectin, formed defective invadopodia and focal adhesions with weakened FAK/SRC signaling. SNAI1 knockout cells performed ineffective receptor-mediated internalization, including nanoparticle and extracellular vesicle (EV) uptake, exhibited reduced lysosomal content, lacked multivesicular bodies enriched in intraluminal vesicles and showed decreased EV secretion. Gain-of-function experiments demonstrated that SNAI1 has an impact on the PSD4/ARF6 signaling module, using FOXA1 as an intermediate factor to regulate EV release by tumor cells. We propose that the SNAI1-FOXA1 transcriptional mechanism operates at the level of membrane and vesicular trafficking control, which interlinks cell plasticity, adhesion and invasiveness through the extracellular environment, with the associated process of EV secretion.
Insights
The transcription factor SNAI1 regulates cancer cell plasticity and invasiveness by controlling membrane trafficking. SNAI1 impacts cell adhesion and extracellular vesicle (EV) secretion through the FOXA1 transcription factor.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Transcription factor SNAI1 is crucial for cancer cell plasticity and invasiveness.
- Understanding SNAI1's regulatory mechanisms is key to targeting cancer progression.
Purpose of the Study:
- To investigate the role of SNAI1 in regulating cell adhesion, endocytosis, and extracellular vesicle (EV) secretion.
- To elucidate the molecular mechanisms by which SNAI1 influences these cellular processes, particularly in triple-negative breast cancer.
Main Methods:
- Genome-wide transcriptomic analysis of SNAI1 knockout breast cancer cells.
- Functional screening of differentially expressed genes and investigation of protein interactions.
- Cellular assays assessing adhesion, invadopodia formation, endocytosis, and EV dynamics.
Main Results:
- SNAI1 knockout led to downregulation of integrin-based adhesion and endocytic components.
- SNAI1 represses FOXA1, which in turn regulates ARF6/PSD4 signaling and impacts integrin/MMP gene expression.
- SNAI1 knockout cells showed impaired adhesion, defective focal adhesions, reduced endocytosis, and decreased EV secretion.
Conclusions:
- The SNAI1-FOXA1 transcriptional axis controls membrane and vesicular trafficking.
- This mechanism links cell plasticity, adhesion, and invasiveness with extracellular vesicle secretion in cancer cells.
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