- Title
- The role of tumour microenvironment in ovarian cancer
- Creator
- Brown, Yazmin
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2024
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- High-grade serous ovarian cancer (HGSOC), the most lethal gynaecological cancer, is known as the “silent killer” of post-menopausal women due to its insidious progression and poor survival statistics. Despite its notorious reputation, there is currently no effective population-based early screening test. The lack of screening test is partly because the early events and mediators of HGSOC carcinogenesis are still being defined. In addition, standard first-line chemotherapy for HGSOC, comprised of carboplatin and paclitaxel, has not changed in the past three decades. The efficacy of this chemotherapy is transient with most patients eventually developing chemoresistance resulting in treatment failure. Therefore, in addition to an early screening test, more effective and durable treatment options are needed to improve patient survival. It is now well established that the extracellular matrix (ECM), a component of the tumour microenvironment, is dysregulated in cancer and is implicated in cancer initiation and drug resistance. This three-dimensional (3D) protein structure not only confers architecture to organ tissues but also dynamically interacts with cells to modulate their behaviour. Consequently, when the ECM is dysregulated, so too is cell behaviour, as seen in cancer. However, the role of ECM in HGSOC development, metastatic progression and drug resistance is currently not well understood. To appreciate pathological changes in the ECM associated with HGSOC and identify potential ECM biomarkers for diagnosis or drug targets, knowledge of what constitutes the normal matrix at the site of origin is a necessary first step. Contrary to its name, most cases of HGSOC are now thought to arise from the distal fallopian tube epithelium rather than the ovarian surface epithelium. For this reason, we have comprehensively characterised and compared the global ECM composition (‘matrisome’) of the benign human distal fallopian tube and HGSOC. This discovery study was achieved using an established proteomic pipeline involving decellularisation/homogenisation of tissues, ECM enrichment, mass spectrometry analysis followed by annotation of the constituent ECM proteins. In addition, we profiled and analysed the top abundant cytosolic and nuclear proteins from the same patient samples of normal and cancer tissue with the rationale of identifying potential functional or biological roles of the ECM from outside-in signalling. To understand the functional significance of a particular ECM protein in HGSOC it is helpful to first understand its role in normal fallopian tube physiology. Fibulin-3, an ECM glycoprotein encoded by EFEMP1, has apparent duality as either a tumour suppressor or tumour promoter depending on the cancer type, and little is known about its role in HGSOC. Therefore, using a genetically modified fibulin-3 (Efemp1) knockout mouse model and organoid model, we examined the influence of fibulin-3 on oviduct (fallopian tube) epithelial cell dynamics. In wild-type mice, mRNA expression of Efemp1 in oviducts became more pronounced with ageing. In line with this observation, knocking out this single ECM protein was observed to cause defective oviductal morphology that was most obvious in the aged cohort. However, further studies with a larger aged cohort are required to confirm this observation. In addition, fibulin-3 mutant mice were subfertile compared to controls, supporting this ECM protein plays an important role in normal reproductive function. In conclusion, by defining the matrix landscape of HGSOC and its purported site of origin, we have established a reliable and comprehensive ECM signature of the benign fallopian tube and identified a set of potential ECM biomarkers that with further investigation may lead to a new paradigm of detection or treatment for HGSOC through targeting the ECM.
- Subject
- high grade serous ovarian cancer; extracellular matrix; STIC; fallopian tube; chemoresistance
- Identifier
- http://hdl.handle.net/1959.13/1510550
- Identifier
- uon:56426
- Rights
- This thesis is currently under embargo and will be available from 14.03.2025, Copyright 2024 Yazmin Brown
- Language
- eng
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