Abstract
Simple SummaryKallikrein-related peptidases have tumour-biological roles and are dysregulated in many cancers. Only a few studies have reported their upregulation in pancreatic cancer and linked them to poor prognosis. By interrogating publicly available and our own datasets, we studied their expression in patient-derived tissues and pancreatic cancer cells. We found several kallikrein-related peptidases that were upregulated, in particular kallikrein-related peptidase 6 at the forefront of the tumour area. We then tested the effect of a kallikrein-related peptidase 6 inhibitor on cancer cell functions. Because the majority of patients present with inoperable disease, a targeted therapeutic intervention may have a positive impact on the survival of this patient population.As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.
Highlights
Pancreatic tumours are cancers of substantial unmet needs, with less than 10% of patients surviving 5 years after diagnosis [1]
Was carried out through the TCGA research network [22]. Interrogating this dataset, we found that KLK1, KLK6, KLK7, KLK8, KLK10 and KLK11 were highly upregulated in Pancreatic ductal adenocarcinoma (PDAC) tissues (Figure 1a)
We found that KLK6, KLK7, KLK8, KLK10 and KLK11 were significantly upregulated in PDAC compared to normal pancreas tissues, while KLK1 levels did not differ between
Summary
Pancreatic tumours are cancers of substantial unmet needs, with less than 10% of patients surviving 5 years after diagnosis [1]. The efficacy of therapeutics and the treatment of PDAC is hampered by the fibrotic tumour stroma, which is made up of a dense and crosslinked extracellular matrix (ECM), and the heterogeneity within tumours and between patients [2]. The standard-of-care treatment of advanced disease is a combination of gemcitabine and nab-paclitaxel, which prolongs patient survival by only a few months. Metastatic disease burden is a primary cause of death in patients with PDAC; treatments aimed at preventing the dissemination of tumour cells may be an alternative therapeutic approach. Treatment responses and disease progression are mediated by the tumour microenvironment (TME), which is a complex and dynamic niche that interlinks various cell populations, the ECM, secreted factors and signalling molecules [4]
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