The role of tetraspanin 6 in colorectal cancer

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Andrijes, Regina (2019). The role of tetraspanin 6 in colorectal cancer. University of Birmingham. Ph.D.

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Abstract

Colorectal cancer is one of the most common cancer types and the second leading cause of cancer-related deaths worldwide. Poor survival of patients highlights the importance of identification of novel prognostic markers. The work in this thesis presents Tspan6 as a potential candidate. Tspan6 is a poorly studied member of the tetraspanin family of proteins that has been implicated in cancer initiation, progression and metastasis. The expression of Tspan6 in a cohort of genetically profiled colorectal adenocarcinomas in this study demonstrated that Tspan6 expression is significantly reduced in tumours vs. adjacent non-cancerous tissues. To illustrate the role of Tspan6 in colorectal cancer (CRC) Tspan6 KO mice carrying APCmin/+ allele were generated. It was found that loss of Tspan6 gene accentuates APC-driven tumorigenesis in vivo. Specifically, these animals developed larger numbers of intestinal and colonic polyps. Interestingly, these polyps were significantly bigger in size and presented with a more severe neoplastic phenotype. The RNAseq analysis of polyps derived from APCmin/+ and APCmin/+Tspan6 KO showed substantial enrichment of differentially expressed genes within the MAPK signalling pathway. Additionally, our experiments with intestinal organoids derived from Tspan6 KO mice and a Caco-2 CRC cell model confirmed the important role of Tspan6 in EGFR-dependent signalling in colonic epithelium via a pathway involving autocrine production of TGF-α. Furthermore, it was demonstrated that Tspan6 regulates the production of EVs through the involvement of an adapter protein syntenin-1, an established partner of Tspan6 which is known to play a critical role in biogenesis of multivesicular bodies (MVBs) and exosomal production. Therefore, it is hypothesised that the Tspan6-syntenin-1 complex plays a critical role in suppressing of colorectal tumorigenesis by controlling autocrine secretion of EGFR ligands via extracellular vesicles. The better understanding of the Tspan6-dependent mechanisms of EGFR regulation can underpin further development of EGFR-targeting therapy and improve survival of CRC patients.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):