Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Lynne-Marie Postovit

Abstract

Tumours are not insular masses of proliferating cells, rather tumour cells evolve within a complex local environment complete with matrix, stromal, and immune components. Therefore, successful tumour growth and eventual metastasis is not determined solely by tumour cells themselves, but also by the fitness advantage or disadvantage conferred by their local environment. However, many of our current cancer models are composed solely of tumour cell isolates. As tumour fitness is dependent on the entire local cellular context, we were interested in characterizing the accuracy of cell lines as models of the tumour microenvironment, with a focus on the secreted Frizzled-related protein (SFRP) family of matricellular proteins. To this end, we investigated the transcriptional similarities and differences between cell lines and bulk tumours. We found that the major transcriptional difference between cell lines and their respective bulk tumours was a loss of stromal components in breast cancer, and a loss of immune components in melanoma. Despite the complexity involved in accurately modelling stromal proteins, we anticipate that they play critical roles in tumour progression. The SFRP family of secreted Wnt antagonists has been demonstrated in a variety of cancers to play a critical, though often controversial, role. To unravel some of these complexities, we performed an indepth pan-cancer analysis to map the context-specific associations of SFRP1-5 with patient outcomes, gene silencing, and gene expression signatures. We show that while SFRP1 often associates with tumour suppressive outcomes and functions, SFRP2 and SFRP4 typically associate with a poor prognosis concomitant with the expression of genes associated with epithelial-to-mesenchymal transition. Notably, in melanoma, we show that SFRP1 is associated with poor patient outcomes and regulates pro-tumourigenic in vitro phenotypes. The results presented herein implicate SFRPs in cancer progression in a highly context-dependent manner. Given that the cellular components of the tumour stroma are genetically stable, they provide appealing candidates for cancer therapies.

Available for download on Sunday, July 29, 2018

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