Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Reagents and Antibodies
2.2. Immunohistochemistry
2.3. Ts4-Cre; cApcflox; Smad4flox Mouse Model (TcAS)
2.4. Patient Cohort Tissue Microarray
2.5. Digital Spatial Profiling (DSP, NanoString)
2.6. Transwell Migration Assay
2.7. Subcutaneous Tumor Model
2.8. Statistical Analysis
3. Results
3.1. Loss of SMAD4 in Murine Intestinal Tumors Is Associated with Increased Activin, pAKT, and CD4 and Decreased Survival
3.2. Increased Activin Expression Is Required for TGF-β-Associated Improvements in Patient Outcome in Stage II or III CRC
3.3. Activin Co-Localizes with Both Tumor and Immune Cells in the TME to Generate Activin-Dependent Signaling Compartments
3.4. Markers of Tumoral and Stromal Compartments Confirm Successful Segregation of Regions with an Increase in CD45 Observed in Activin (−) Regions of the Stroma
3.5. Activin Stimulates T-Cell Suppression and APC Activation in the Stromal Compartment of the TME in CRC
3.6. Activin Co-Localization Is Associated with Increased Activation of PI3K/AKT Signaling to Enhance Tumor Cell Migration and Growth
4. Discussion
4.1. SMAD-Independent Signaling in CRC
4.2. TGF-β, Activin, and CD4 in Human CRC
4.3. Activin Co-Localization with Fibroblasts and Immune Cells
4.4. Activin Signaling in the Tumor Cells
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Wiley, M.B.; Bauer, J.; Mehrotra, K.; Zessner-Spitzenberg, J.; Kolics, Z.; Cheng, W.; Castellanos, K.; Nash, M.G.; Gui, X.; Kone, L.; et al. Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance. Cancers 2023, 15, 3003. https://doi.org/10.3390/cancers15113003
Wiley MB, Bauer J, Mehrotra K, Zessner-Spitzenberg J, Kolics Z, Cheng W, Castellanos K, Nash MG, Gui X, Kone L, et al. Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance. Cancers. 2023; 15(11):3003. https://doi.org/10.3390/cancers15113003
Chicago/Turabian StyleWiley, Mark B., Jessica Bauer, Kunaal Mehrotra, Jasmin Zessner-Spitzenberg, Zoe Kolics, Wenxuan Cheng, Karla Castellanos, Michael G. Nash, Xianyong Gui, Lyonell Kone, and et al. 2023. "Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance" Cancers 15, no. 11: 3003. https://doi.org/10.3390/cancers15113003