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Title: Characterisation of paracrine Wnt regulators in colorectal cancer microenvironment
Author: Lee, Sang Eun
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Aberrant Wnt activation is commonly found in colorectal cancer (CRC), especially in cells adjacent to the tumour microenvironment (TME). This indicates the crucial interaction between tumour cells and their niche. Comprehensive transcriptomic analyses by the Cancer Genome Atlas project show genes that are differentially upregulated in tumour stromal population. Of these, a cluster of genes includes markers of cancer-associated fibroblasts (CAFs) that are associated with poor survival. I hypothesise that a subset of CRCs is dependent on paracrine Wnt activation from the surrounding CAFs for tumour progression. PERIOSTIN (POSTN) is a matricellular protein that is often upregulated in CAFs and is associated with poor CRC prognosis. Human primary fibroblasts established from CRC tissues are found to retain transcriptomic and functional profiles that are distinct between normal and cancer-associated populations in vitro, including POSTN upregulation in CAFs. In vitro gain-of-function studies show that POSTN potentiates Wnt activation in Wnt ligand-dependent manner, and promotes Wnt receptor stabilisation via yet unclear mechanism(s) interacting with Wnt components on cell membrane. To better study paracrine Wnt activation, a 3D model is developed in which intestinal epithelial cells reside on top of fibroblasts. Co-culture of normal small intestinal epithelial cells with normal fibroblasts show an organised, differentiated crypt/villi-like structure of the epithelial layer, whereas disorganised multi-layered epithelial cells with altered polarity are observed with CAFs. Moreover, the contribution of CAF-derived POSTN in tumour progression is assessed utilising the 3D model system and in vivo xenograft formation approaches. This project demonstrates POSTN is upregulated in CRC and acts as a potential CAF-derived Wnt regulator, providing insight into a novel Wnt regulation that may be at play in CRC tumour progression. The tissue-engineered 3D co-culture system will be a useful tool to study different cell type interactions without sacrificing biomimetic organisation by providing a simple and malleable system.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available