Modelling Juxtacrine Mediated Tumor-Fibroblast Interactions in Three-Dimensional Co-Cultures of Pancreatic Ductal Adenocarcinoma
Date of Award
Open Access Thesis
Master of Science (MS)
Mohamed A. Gharbi
Joanna B. Dahl
The tumor-microenvironment is a rich and complex milieu of mutated cancer cells and otherwise healthy cells engaged in dynamic interactions. Fibroblasts, the most abundant cellular component of human connective tissues, are implicated in a tumor promoting process known as stromal crosstalk. This stromal crosstalk is driven by numerous signaling pathways including contact mediated juxtacrine signaling and directed long distance paracrine signaling. Recent research suggests these signaling pathways are particularly important for two distinct types of fibroblasts. Mayofibroblastic cancer associated fibroblasts (MyCAFs) are associated with tumor suppression and shown to rely primarily on juxtacrine signaling, while inflammatory cancer associated fibroblasts (iCAFs) are associated with tumor promotion and have been shown to rely on paracrine signaling in the tumor microenvironment. In this thesis two 3D co-culture platforms are utilized to model paracrine and juxtacrine signaling between pancreatic ductal adenocarcinoma (PDAC) and iCAF-like fibroblasts vs MyCAF-like fibroblasts. These studies implicate juxtacrine signaling as the primary mediator of in vitro tumor-fibroblast contractility. We further apply our juxtacrine model to differentiate fibroblast contractility in drug resistant vs. drug naïve PDAC co-cultures and observe drug resistant PDAC co-cultures exhibit a muted contractile response compared to drug naïve co-cultures. Finally, we attempt to use macroscopic tumor-fibroblast aggregates generated in juxtacrine experiments to study the effect of stromal depletion by photodynamic therapy on drug delivery. We demonstrate enhanced drug penetration in PDT pretreated PDAC spheroid homocultures, although AOC stromal depletion experiments are inconclusive.
Struth, Eric, "Modelling Juxtacrine Mediated Tumor-Fibroblast Interactions in Three-Dimensional Co-Cultures of Pancreatic Ductal Adenocarcinoma" (2022). Graduate Masters Theses. 755.