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Title: FAK-regulated IL6 reprograms the tumour associated macrophage phenotype and promotes pancreatic tumour growth
Author: Davidson, Catherine Jane
ISNI:       0000 0004 7969 0947
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Pancreatic ductal adenocarcinoma (PDAC) remains a cancer with few effective therapeutic options, and patient prognosis is poor. Immunotherapy has yet to yield significant benefit in treatment of PDAC. Understanding the key molecular pathways that drive resistance to immunotherapy may enable development of new therapeutic strategies for this cancer of unmet clinical need. The non-receptor protein tyrosine kinase, Focal Adhesion Kinase (FAK), is up-regulated in PDAC, and recent studies have identified an important role for FAK in regulating the fibrotic and immunosuppressive pancreatic tumour microenvironment (TME). However, the mechanisms underpinning FAK-dependent regulation of the immunosuppressive TME remain poorly understood. Using CRISPR, I have depleted FAK expression in pancreatic cancer cells isolated from PDAC arising on LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice (KPC mice), and show that FAK-depletion results in a tumour growth delay that is associated with reprogramming of the tumour associated macrophage (TAM) phenotype. Mechanistically I identify FAK-dependent regulation of interleukin-6 secretion from pancreatic cancer cells as an important regulator of the TAM phenotype, and further show that this axis requires CD4+ T-cells. These results provide new insights into the complexity of FAK-dependent immune regulation in cancer, and support continued evaluation of FAK kinase inhibitors in combination with immunotherapy for the treatment of PDAC.
Supervisor: Serrels, Alan ; Anderton, Stephen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: pancreatic cancer ; M2 macrophages ; M1 macrophages ; Focal Adhesion Kinase ; FAK