Protease-activated receptor 1 drives and maintains ductal cell fates in the premalignant pancreas and ductal adenocarcinoma.

Pancreatic acinar cells have high plasticity and can transdifferentiate into ductal-like cells. This acinar-to-ductal metaplasia (ADM) contributes to tissue maintenance but may also contribute to the premalignant transformation that can eventually progress to pancreatic ductal adenocarcinoma (PDAC). Macrophages are key players in ADM, and macrophage-secreted matrix metalloproteinase (MMP)-9 induces ADM through yet unknown mechanisms.

Early macrophage infiltrates impair pancreatic cancer cell growth by TNF-α secretion.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a grim disease with high mortality rates. Increased macrophage influx in PDAC is a common hallmark and associated with poor prognosis. Macrophages have high cellular plasticity, which can differentiate into both anti- and pro-tumorigenic properties.

Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation.

Purpose: Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored.

Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression.

High-grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF-1.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high-grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear.

PAR1 signaling on tumor cells limits tumor growth by maintaining a mesenchymal phenotype in pancreatic cancer.

Protease activated receptor-1 (PAR1) expression is associated with disease progression and overall survival in a variety of cancers. However, the importance of tumor cell PAR1 in pancreatic ductal adenocarcinomas (PDAC) remains unexplored. Utilizing orthotopic models with wild type and PAR1-targeted PDAC cells, we show that tumor cell PAR1 negatively affects PDAC growth, yet promotes metastasis.