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Type: Thesis
Title: Investigating the Contribution of Specific Cancer-Associated Fibroblast Subsets to Colorectal Tumourigenesis
Author: Gieniec, Krystyna Anna
Issue Date: 2020
School/Discipline: Adelaide Medical School
Abstract: Despite colorectal cancer (CRC) remaining a prominent cause of cancer death worldwide, there is little known about how the surrounding connective tissue ‘stroma’ specifically encourages poorer prognosis. While many studies have attempted to interrogate the molecular cross-talk between the tumour and stromal cancer-associated fibroblasts (CAFs), the most important tumour-promoting interactions remain ill-defined. We are yet to adequately exploit these pathways for the prevention and treatment of CRC. In this thesis I aimed to identify and test specific CAF subsets for their putative ability to promote CRC, both in vitro and in vivo. Through RNA-sequencing, prognostic analyses and immunohistochemistry, I identified Melanoma cell adhesion molecule (MCAM) as a candidate CRC-promoting stromal factor that was significantly associated with worse patient prognosis. MCAM expression was significantly upregulated in mouse and human CRC compared to normal colon tissue and marked proliferative tumour-associated stroma comprised of both endothelial and fibroblast cell populations in vivo. Upon overexpression in primary mouse colon fibroblasts in vitro, MCAM significantly reduced contractile activity and enhanced migration. I also developed immunocompetent mouse models of primary and metastatic CRC to examine the efficacy of an inhibitor of a known CRC-promoting stromal factor, Gremlin1 (GREM1). These mouse models involved the implantation of mouse colorectal tumour organoids directly into the colon wall via colonoscope or into the liver via the portal vein, and the tumours generated represented human disease both genetically and pathologically. If we can better understand CAF biology and heterogeneity, and identify specific tumour-promoting CAF subtypes, then we can develop more targeted therapeutic strategies that inhibit both the cancer and its enhancing stroma to ultimately improve CRC patient survival.
Advisor: Butler, Lisa
Woods, Susan
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2021
Keywords: Colorectal cancer
cancer-associated fibroblasts
tumour-promoting stroma
tumour organoids
Provenance: This thesis is currently under Embargo and is not available.
Appears in Collections:Research Theses

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