Background Cancer-associated fibroblasts present a significant barrier to standard of care immunotherapy through multiple mechanisms including deposition of extracellular matrix, reciprocal signaling with cancer cells, and crosstalk with tumor-infiltrating lymphocytes. The peptidyl-prolyl isomerase Pin1 is an enzyme that catalyzes the cis-trans isomerization of peptidyl-prolyl peptide bonds in phosphorylated proteins, thus playing a crucial role in cellular functions including cell growth and differentiation. Recent evidence points to a key immunosuppressive role for Pin1 in cancer-associated fibroblasts in pancreatic cancer.1 The present study aimed to further investigate the role of Pin1 in modulating fibroblast phenotypes and regulating the TGF-beta signaling pathway.
Methods Our research employed a set of in vitro experiments with Pin1-targeting strategies applied to various fibroblast cell lines. The impact on the fibroblast phenotypes and the TGF-beta signaling was assessed through a detailed cell phenotype and protein analysis using a combination of imaging analysis, ELISA, and Western Blot techniques.
Results The data revealed that interventions targeting Pin1 significantly modulated the phenotype of fibroblasts, steering them away from a pro-tumorigenic state. Furthermore, we found that Pin1 acts as a positive regulator of TGF-beta signaling, a key pathway often dysregulated in cancer progression and metastasis.
Conclusions The results of our study emphasize the significant role of Pin1 in influencing critical cellular and molecular mechanisms within cancer. By altering cancer-associated fibroblast phenotype and positively regulating TGF-beta signaling, Pin1 presents a promising target for therapeutic interventions. Our findings advance the current understanding of Pin1’s role in cancer biology, supporting the need for further exploration of Pin1-targeted treatment strategies.
Koikawa K, Kibe S, Suizu F, et al. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy. Cell. 2021;184(18):4753–4771.e27. doi:10.1016/j.cell.2021.07.020
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