Inclusion of cancer-associated fibroblasts in drug screening assays to evaluate pancreatic cancer resistance to therapeutic drugs

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterised by a pro-inflammatory stroma and multi-faceted microenvironment that promotes and maintains tumorigenesis. However, the models used to test new and emerging therapies for PDAC have not increased in complexity to keep pace with our understanding of the human disease. Promising therapies that pass pre-clinical testing often fail in pancreatic cancer clinical trials. The objective of this study was to investigate whether changes in the drug-dosing regimen or the addition of cancer-associated fibroblasts (CAFs) to current existing models can impact the efficacy of chemotherapy drugs used in the clinic. Here, we reveal that gemcitabine and paclitaxel markedly reduce the viability of pancreatic cell lines, but not CAFs, when cultured in 2D. Following the use of an in vitro drug pulsing experiment, PDAC cell lines showed sensitivity to gemcitabine and paclitaxel. However, CAFs were less sensitive to pulsing with gemcitabine compared to their response to paclitaxel. We also identify that a 3D co-culture model of MIA PaCa-2 or PANC-1 with CAFs showed an increased chemoresistance to gemcitabine when compared to standard 2D mono-cultures a difference to paclitaxel which showed no measurable difference between the 2D and 3D models, suggesting a complex interaction between the drug in study and the cell type used. Changes to standard 2D mono-culture-based assays and implementation of 3D co-culture assays lend complexity to established models and could provide tools for identifying therapies that will match clinically the success observed with in vitro models, thereby aiding in the discovery of novel therapies.

Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

“…Similar to our results, Monteiro et al prepared an in vitro PDAC multicellular model with a ratio of mouse PDAC cells to human CAF ratio of 8:2 [ 32 ]. Another study reported that an increase in the CAF ratio could ultimately affect the susceptibility of tumor models to anticancer agents [ 33 ]. Since we aimed to see tissue level changes by environmental stress and fibrosis signaling stimulation, we determined the cell ratio that can maximize the phenotype of each cell component as the spheroid formation ratio.…”

Indole Diketopiperazine Alkaloids from the Marine Sediment-Derived Fungus Aspergillus chevalieri against Pancreatic Ductal Adenocarcinoma

“…In contrast to the standard-of-care treatment paclitaxel, for which IC 50 values in the low nanomolar range are reported [33], compounds 1 and 4 display only moderate cytotoxic efficacy levels, with IC 50 values of 25.8 and 23.4 µM, respectively.…”

Pyruvate and uridine rescue the metabolic profile of OXPHOS dysfunction

“…We can, however, not exclude that, we may have missed more discrete beneficial effects of some of the tested treatment strategies since many factors play a role in the cell cycle regulation and thus proliferation [ 46 , 47 ]. We can also not exclude that the intracellular delivery of the nutrients, the chosen dosages or the possible metabolization in our disease model (fibroblasts) was not optimal and that those therapies might have a positive effect on other symptoms or in other disease models [ 48 ].…”