Impact of pancreatic proenzymes on pancreatic ductal adenocarcinoma associated fibroblasts

The tumor microenvironment (TME) plays a pivotal role in tumor initiation, progression, and the formation of pre-metastatic niches. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma containing a significant enriched population of cancer-associated fibroblasts (CAFs). The interplay between CAFs and tumor cells is crucial in driving tumor advancement and metastasis, underscoring the potential benefits of novel therapeutic strategies targeting stromal cells to improve patient survival. Pancreatic (pro)enzymes have shown efficacy in cancer treatment. In this study, we evaluated a formulation of Trypsinogen and Chymotrypsinogen A (PRP) on a model of PDAC-CAFs dynamics. Our findings demonstrated PRP multifaceted effects, including: (i) inhibition of the acquisition of a pro-tumoral phenotype by normal fibroblasts; (ii) enhanced expression of E-cadherin and decreased expression of epithelial-mesenchymal transition (EMT)-associated genes; (iii) blockade of the crosstalk between CAFs and cancer cells, leading to a decrease in the proliferation and migration rate of the pancreatic cancer cells; (iv) modulation of CAFs-induced alteration on endothelial cells; (v) induction of Meflin expression, associated with a less pro-tumoral phenotype; (vi) inhibition of the TGF-β pathway, reducing the activation of Smad2/3 proteins involved in fibroblast phenotypic alteration; (vii) selective induction of apoptosis in CAFs by PRP, as evidenced by increased expression of the BAX biomarker; (viii) impaired fibrotic tissue formation, as tested in an in vivo model of PDAC, by reducing the population of CAFs within the TME. Collectively, these results underscore the potential of PRP as a therapeutic candidate for disrupting the intricate interactions within the PDAC TME. Further research and clinical investigations are necessary to validate the translational potential of PRP as an adjunct therapy for PDAC.