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

Abstract

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. As we previously identified MMP9 as a novel agonist of protease-activated receptor 1 (PAR1), a receptor that is known to orchestrate the cross-talk between macrophages and tumor cells in PDAC, we here assessed the contribution of PAR1 to pancreatic cell fates. We found that genetic deficiency for PAR1 increases acinar gene expression programs in the healthy pancreas and that PAR1 deficiency limits ductal transdifferentiation in experimental systems for ADM. Moreover, PAR1 silencing in PDAC cells increases acinar marker expression. Changes in PDAC cell lines were associated with a downregulation of known Myc-target genes, and Myc inhibition mimics PAR1 deficiency in enhancing acinar programs in healthy organoids and PDAC cells. Overall, we identify the PAR1-Myc axis as a driver of ductal cell fates in premalignant pancreas and PDAC. Moreover, we show that cellular plasticity is not unique to acinar cells and that ductal regeneration into acinar-like cells is possible even in the context of oncogenic KRAS activation.

Subtype Transdifferentiation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression

“…This suggests that also ductal cells are plastic and able to regenerate into acinar-like cells, even in the presence of oncogenic KRAS activation. PAR1-Myc axis inactivation leads to increased expression levels of PTF1A and MIST1, whereas expression levels of SOX9 and KRT19 decrease [132]. Moreover, macrophages infiltrating the pancreas drive ADM by secreting inflammatory cytokines RANTES and TNF-α, which induce ADM through activation of NF-κB and its target genes, including MMPs, involved in regulating survival, proliferation, and degradation of extracellular matrix [133] (Figure 4).…”