Fluid shear stress enhances pancreatic cancer motility through YAP activation

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate due to late-stage diagnosis. Although SUIT2 sublines differ in metastatic and drug-resistant behavior, the mechanisms behind these differences are unclear. Fluid shear stress can regulate tumor cell migration, and the mechanosensitive factor yes-associated protein (YAP) promotes PDAC progression. However, the impact of shear stress on YAP signaling in PDAC cells remains unknown. This study aims to better understand how fluid shear stress influences the behavior of PDAC cells and to elucidate the mechanisms by which shear stress regulates their metastatic potential, in order to support the development of more effective therapeutic strategies.

Using the BioFlux-Shear-Flow-System, we observed that under static conditions, the more metastatic SUIT2-007 cells displayed greater migratory capacity than the less metastatic SUIT2-028 cells. However, exposure to fluid shear stress significantly enhanced the migration capacity of SUIT2-028 cells. Consequently, the migratory capacities of the two cell lines became comparable under shear stress conditions. RNA-sequencing revealed differences in yes-associated protein (YAP) activation between SUIT2-028 and SUIT2-007. Functional assays using a YAP activation inhibitor and scratch assay demonstrated that inhibition of YAP activity reduced migration in both tumor cell lines and abolished the differences in their migratory capacities.

Our findings highlight YAP as a mechanosensitive regulator of pancreatic cancer cell migration under shear stress, offering insights into how biomechanical forces can drive metastatic capacity.