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Activin A balance regulates epithelial invasiveness and tumorigenesis
Grégoire F Le Bras1, Holli A Loomans2, Chase J Taylor1
1Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
Abstract:
Activin A (Act A) is a member of the TGFβ superfamily. Act A and TGFβ have multiple common downstream targets and have been described to merge in their intracellular signaling cascades and function. We have previously demonstrated that coordinated loss of E-cadherin and TGFβ receptor II (TβRII) results in epithelial cell invasion. When grown in three-dimensional organotypic reconstruct cultures, esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TβRII showed activated Smad2 in the absence of functional TβRII. However, we could show that increased levels of Act A secretion was able to induce Smad2 phosphorylation. Growth factor secretion can activate autocrine and paracrine signaling, which affects crosstalk between the epithelial compartment and the surrounding microenvironment. We show that treatment with the Act A antagonist Follistatin or with a neutralizing Act A antibody can increase cell invasion in organotypic cultures in a fibroblast- and MMP-dependent manner. Similarly, suppression of Act A with shRNA increases cell invasion and tumorigenesis in vivo. Therefore, we conclude that maintaining a delicate balance of Act A expression is critical for homeostasis in the esophageal microenvironment.
Insights
Maintaining a balance of Activin A (Act A) is crucial for esophageal homeostasis. Loss of Act A promotes cell invasion and tumorigenesis, highlighting its role in tissue regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Activin A (Act A) is part of the TGFβ superfamily, sharing signaling pathways.
- Loss of E-cadherin and TGFβ receptor II (TβRII) promotes epithelial cell invasion.
- Act A signaling influences crosstalk between epithelial cells and their microenvironment.
Purpose of the Study:
- To investigate the role of Activin A in esophageal epithelial cell behavior.
- To understand the impact of Act A on Smad2 phosphorylation and cell invasion.
- To determine the necessity of Act A balance for maintaining esophageal homeostasis.
Main Methods:
- Organotypic reconstruct cultures of esophageal keratinocytes.
- Use of dominant-negative mutants for E-cadherin and TβRII.
- Employing Act A antagonists (Follistatin, antibodies) and shRNA for Act A suppression.
- In vivo tumorigenesis assays.
Main Results:
- Esophageal keratinocytes with defective E-cadherin/TβRII showed Smad2 activation and increased Act A secretion.
- Act A secretion induced Smad2 phosphorylation.
- Inhibition of Act A (via Follistatin or antibody) increased cell invasion in organotypic cultures.
- Suppression of Act A via shRNA led to increased cell invasion and tumorigenesis in vivo.
Conclusions:
- A balanced level of Activin A is critical for maintaining esophageal microenvironment homeostasis.
- Dysregulation of Act A contributes to increased cell invasion and tumorigenesis.
- Act A plays a significant role in regulating epithelial cell behavior and tissue integrity.
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