Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is a devastating disease. New tools which can aid in the understanding of PDAC biology and novel drug development are needed. We established an in vitro fibroblast model in combination with collagen biomarkers as a translational anti-fibrotic drug screening tool. Furthermore, we assessed the prognostic value of the collagen biomarkers in patients with PDAC. We found that collagen biomarkers quantify fibroblast activity in vitro and predict the survival rate in patients with pancreatic ductal adenocarcinoma.The use of novel tools to understand tumour-fibrosis in pancreatic ductal adenocarcinoma (PDAC) and novel anti-fibrotic treatments are highly needed. We established a pseudo-3D in vitro model including humane pancreatic fibroblasts (PFs) and pancreatic cancer-associated fibroblasts (CAFs) in combination with clinical collagen biomarkers, as a translational anti-fibrotic drug screening tool. Furthermore, we investigated the prognostic potential of serum collagen biomarkers in 810 patients with PDAC. PFs and CAFs were cultured in Ficoll-media. Cells were treated w/wo TGF-ß1 and the anti-fibrotic compound ALK5i. Biomarkers measuring the formation of type III (PRO-C3) and VI (PRO-C6) collagens were measured by ELISA in supernatant at days 3, 6, 9, and 12. PRO-C3 and PRO-C6, and their association with overall survival (OS), were evaluated in serum with PDAC (n = 810). PRO-C3 and PRO-C6 were upregulated in CAFs compared to PFs (p < 0.0001.). TGF-ß1 increased PRO-C3 in both PFs and CAFs (p < 0.0001). The anti-fibrotic compound ALK5i inhibited both PRO-C3 and PRO-C6 (p < 0.0001). High serum levels of PRO-C3 and PRO-C6 in patients with PDAC were associated with short OS (PRO-C3: HR = 1.48, 95%CI: 1.29–1.71, p < 0.0001 and PRO-C6: HR = 1.31, 95%CI: 1.14–1.50, p = 0.0002). PRO-C3 and PRO-C6 have the potential to be used both pre-clinically and clinically as a measure of tumor fibrosis and CAF activity.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of 10% [1]
We investigated the prognostic potential of serum PRO-C3 and PRO-C6 in patients with PDAC, to evaluate the translational value of the PDAC scar-in-a-jar model (SiaJ) model
On day 3, there was no difference in PRO-C3 levels between pancreatic fibroblasts (PFs)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of 10% [1]. Two main reasons for the poor outcome of patients with PDAC are late diagnosis in advanced disease stages and poor efficacy of interventions [2,3]. 80% of patients present with locally advanced or metastatic disease at the time of diagnosis and are not eligible for surgery. Standard of care for these patients is limited to conventional chemotherapies, which give only minimal, or no, overall survival (OS) benefit [3,4,5,6,7]. One factor that contributes significantly to the high resistance to chemotherapy in PDAC is the extensive stromal entity in the tumor. The PDAC stroma may comprise up to
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