Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Simple Summary Kallikrein-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, alpha SMA 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.