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Title: Modelling the interactions between pancreatic tumour cells and cancer-associated fibroblasts : enhancing models for drug development
Author: Brumskill, S.
ISNI:       0000 0004 7428 654X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Pancreatic ductal adenocarcinoma (PDAC) is characterised by a complex tumour supportive microenvironment including a dense fibrotic stroma (Farrow et al., 2008). Embryonic signalling pathways such as the Hedgehog (Hh) and Wnt pathway are involved in the interactions between cancer-associated fibroblasts (CAFs) and pancreatic tumour cells as well as maintenance of the tumour supportive microenvironment (Bailey et al., 2008, Zhang et al., 2013). Prognosis for PDAC remains poor (global 5 year survival rate of less than 10% (Siegel et al., 2015)) owing, in part, to limited therapy options available and resistance to current therapies. The tumour microenvironment has been implicated in chemotherapy resistance (Dauer et al., 2017, Hessmann et al., 2017) which has led to a need for drug screening techniques which include elements of the tumour microenvironment. I therefore sought to develop a co-culture model incorporating CAFs and epithelial cells that would better represent the tumour microenvironment. This model would enable the study of embryonic signalling pathways and how these may be exploited in the treatment of PDAC. Mixed 3D cultures of CAFs and cancer cell lines showed a morphology close to that of a tumour with the presence of CAFs dispersed throughout the spheroid. The Hh pathway was found to be upregulated in CAFs in 2D co-cultures of CAFs and PDAC cancer cell lines. The Wnt pathway was found to be upregulated in PANC1 cells in a 2D co-culture of CAFs and PANC1 cells. This demonstrated that the embryonic signalling pathways (Hh and Wnt) are involved in the cross talk between CAFs and PDAC tumour cells. 2D, co-culture of CAFs with PANC1 cells reduced sensitivity to gemcitabine, dependent upon the number of CAFs when compared to the monoculture of the PANC1 cells. Furthermore, when SUIT2 and BXPC3 cell lines were cultured in a 3D model, the presence of CAFs significantly reduced the efficacy of gemcitabine effectively conferring resistance. Together these results demonstrate a complex interaction between CAFs and PDAC tumour cells in an in vitro model that is similar to the in vivo microenvironment. In addition the presence of CAFs within 2D and 3D co-culture models has a considerable impact on pancreatic cancer cell resistance to gemcitabine and thus better reflects the clinical response. The difference in gemcitabine sensitivity between mono- and co-culture together with the more physiologically relevant morphology in the co-cultured spheroids, highlights the importance of in vitro drug screening techniques which better represent the tumour microenvironment in order to more accurately predict a compound's clinical efficacy.
Supervisor: Costello-Goldring, Eithne ; Greenhalf, William ; Calcraft, Peter ; Phillips, Caroline Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral