University of Cambridge
Regulation of Wnt signalling in ovarian cancer and immune cells
Abstract
dc:description.abstractWnt signalling is an ancient, highly conserved, and tightly regulated pathway involved in embryogenesis, cell polarity, and migration. Dysregulation of Wnt signalling is associated with abnormal cellular growth contributing to cancer formation. Especially in colorectal cancer (CRC) mutations in the Wnt pathway that enhance signalling are driving forces for tumour formation and progression. Besides the effects on polarity and migration, upregulation of Wnt signalling is associated with decreased immune infiltration, commonly associated with low overall survival and progression free survival. Ovarian cancer is driven by mutations in TP53, BRCA1, and BRCA2, and is characterised by genomic instability leading to complex genomic alterations. In a small patient cohort study, the Miller laboratory had previously linked mutations in the negative regulators of the Wnt pathway, Dkk1 and Nkd1, with decreased immune infiltration in ovarian cancers. To interrogate the functional importance of these negative regulators further, I knocked out and expressed Dkk1 and Nkd1 in murine ovarian cancer models ID8 p53 / and UPK10. Overexpression of mutated Dkk1 and Nkd1 does not affect in vitro or in vivo growth. Unexpectedly, overexpression of wild-type Dkk1 and Nkd1 leads to reduced growth in immunocompetent mouse strains. Injection into immunocompromised hosts leads to enhanced growth of wild type Dkk1- and Nkd1-overexpressing tumour cells, potentially caused by the lack of anti tumour CD8+ and/or NK cell activity. In the second half of my thesis, I explore the role of Wnt signalling in the immune system. Immune cells, particularly cytotoxic CD8 T cells, play a pivotal role in tumour clearance by specifically recognising and eliminating tumour cells. However, lack of effector functions and persistence in patients are key problems that must be overcome in adoptive T cell therapy. Interestingly, Wnt signalling has been shown to be critical to maintain T cell memory required for persistence and sustained effector function. In this thesis, I investigate the expression of TCF7 and the less studied TCF7L2, both Wnt transcription factors of the TCF/LEF family, in different immune subsets. I focus on the detection and the differential expression of extended and short isoforms of these transcription factors and find unique expression patterns in mRNA and protein. TCF7 expression is detected in memory subsets while TCF7L2 is predominantly expressed in naïve subsets. Modulating expression of short and extended TCF7/TCF7L2 isoforms in immune cells might provide a unique angle to increase performance in the therapeutic settings. Taken together, this thesis investigates the function of negative Wnt regulators in ovarian cancer and explores the differentially expressed isoforms of central Wnt transcription factors in immune subsets.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2024
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Machel, Anne
- Advisors dc:contributor.advisor
-
- de la Roche, Maike
- Gill, Michael
- Miller, Martin
Subjects
dc:subject × 4Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.114216
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/377390