TGFβ1 and RGD Cooperatively Regulate SMAD2/3-Mediated Oncogenic Effects in Prostate Cancer Cells in Bio-Orthogonally...

Area of Science:

• Biomaterials Science
• Cancer Biology
• Cellular Signaling

Background:

• Prostate cancer metastasis is a complex process involving cellular changes and interactions with the microenvironment.
• Understanding the molecular mechanisms driving metastasis is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the role of transforming growth factor beta 1 (TGFβ1) signaling and integrin binding in recapitulating prostate cancer cell metastasis in a 3D hydrogel model.
• To explore the cooperative effects of TGFβ1 and RGD peptides on DU145 prostate cancer cell behavior and phenotype.

Main Methods:

• DU145 prostate cancer cells were cultured in hyaluronic acid-based, protease-degradable hydrogels functionalized with RGD peptides.
• Cells were treated with TGFβ1, and morphological changes, SMAD2/3 nuclear localization, gene expression, and epithelial-to-mesenchymal transition (EMT) were analyzed.
• A TGFβ receptor inhibitor (SB-431542) was used to assess the role of TGFβ1 signaling.

Main Results:

• RGD-conjugated hydrogels, in combination with TGFβ1, induced significant morphological changes and the formation of interconnected cellular networks in DU145 cells.
• TGFβ1 promoted SMAD2/3 nuclear translocation, upregulated target genes, and induced EMT, characterized by loss of epithelial markers and gain of mesenchymal markers.
• Inhibition of TGFβRI/ALK5 attenuated TGFβ1-induced effects, including morphological changes and EMT, and restored epithelial marker expression.

Conclusions:

• Integrin-binding RGD peptides and TGFβ1 signaling cooperatively drive prostate cancer cell aggressiveness and promote tumor progression in a 3D microenvironment.
• The developed hydrogel model effectively recapitulates key aspects of prostate cancer metastasis, offering a platform for further investigation.