Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly malignancy with a very low survival rate. Asymptomatic disease progression, a complex tumour microenvironment (TME) and high resistance to current therapeutic methods, all contribute towards PDAC's dismal statistics. A key challenge towards better understanding of this deadly disease and its therapeutic response is the development of an in vitro disease model that is capable of mimicking the various complex and important features of the PDAC TME such as the biological/cellular, the biochemical as well as the biomechanical/biophysical complexity. We have previously developed a complex multicellular model of PDAC which is a spatially advanced multicellular scaffold that mimics the desmoplasia of PDAC. In this work, we have elucidated the importance/effect of interstitial fluid flow in the model. More specifically, we incorporated our multicellular PDAC model in a dynamic bioreactor for a flow rate of 3.5 ml/min. We exposed the model to flow either short-term (5 days) or long term (14 days). Thereafter we monitored the evolution of the cells under flow as well as their response to chemotherapy, as compared to non-dynamic (static) culture. Overall, fluid flow promoted the mesenchymal and reduced the epithelial cell population in our model, as compared to static conditions. Furthermore, the duration of the flow impacted the functionality of activated stellate cells, i.e., short-term flow promoted a more fibrotic/desmoplastic phenotype while long-term flow reduced the fibrosis, disrupted the deposition of collagen and increased the inflammatory levels. As a result, short-term flow exposure led to higher chemotherapy resistance as compared to long-term flow. This work highlights how dynamic flow can alter key features of in vitro models as well as the importance of flow consideration for increased in vitro biomimicry.
•Dynamic flow affects the desmoplastic reaction in our 3D PDAC model.•Short-term flow promotes fibrosis and chemoresistance in our 3D PDAC model.•Long-term flow is antifibrotic and proinflammatory in our 3D PDAC model.