Sculthorpe, Declan
(2024)
Molecular characterisation of the early metastatic phenotype in colorectal cancer.
PhD thesis, University of Nottingham.
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related mortality, primarily due to its propensity for invasion and metastasis. The progression of CRC involves a series of complex and poorly understood biological events, including tumour invasion into surrounding tissues, lymphovascular infiltration, and the establishment of metastases in regional lymph nodes and distant organs. These processes are critical to understanding CRC's aggressiveness and are of both clinical and biological significance.
This study aimed to elucidate the early metastatic phenotype in CRC through a comprehensive, multi-faceted approach. The study integrated findings from existing literature, insights from collaborative research networks, and data generated from a specifically designed invasive CRC cohort. This cohort was constructed to mimic the stepwise events of tumour invasion and metastasis, providing a unique perspective on the molecular drivers of these processes.
One of the key findings of this research was the identification of ARL8A as a potential tumour suppressor. ARL8A was initially highlighted in The Cancer Genome Atlas (TCGA) series for its possible role in CRC invasive progression. However, our study found that the loss of ARL8A was associated with poor prognostic factors, such as distant metastasis, in CRC patients. Interestingly, functional studies revealed that inhibiting ARL8A reduced CRC cell proliferation, migration, and invasion, suggesting a complex role in CRC progression. This duality highlights the challenges of correlating transcriptomic data with protein expression and functional outcomes, especially within the heterogeneous tumour microenvironment.
Another significant discovery was the role of CLIC4, particularly within the stromal compartment of CRC tumours. Loss of stromal CLIC4 expression was associated with increased tumour aggressiveness, including enhanced cell proliferation and migratory capabilities, indicating that CLIC4 may act as a tumour suppressor in CRC. The study also found that CLIC4 expression was higher in early-stage tumours, suggesting its involvement in initial tumour progression, followed by a potential loss that enhances tumour invasiveness. The interactions between CLIC4 and key signalling pathways, such as the Wnt/β-catenin pathway, further suggest that CLIC4 may influence CRC progression through modulation of c-Myc-mediated apoptosis.
In addition to these findings, the thesis identified several novel biomarkers associated with invasive CRC phenotypes. For example, MUC5B was found to be significantly upregulated in tumours exhibiting vascular invasion (VI) but downregulated in later stages of metastasis. This pattern suggests that MUC5B may be specifically involved in the early establishment of VI, making it a potential marker for early metastatic events. Similarly, REG4 and APCDD1 were identified as key genes upregulated during the transition from VI to nodal invasion, highlighting their potential as biomarkers for detecting these critical early stages of metastasis.
The study also explored the complex molecular networks underlying CRC metastasis, revealing that differentially expressed genes during the metastatic process could form interacting protein clusters. These clusters, particularly those involving the complement system and UDP-glycosyltransferases, were implicated in regulating the tumour microenvironment and promoting metastatic spread. Understanding the epigenetic and genetic changes driving these networks is crucial for developing targeted therapies that could inhibit CRC metastasis. Further research is required to validate these findings in larger, more diverse patient cohorts. Future studies should focus on exploring the roles of identified biomarkers and molecular networks in the tumour microenvironment, using advanced models such as 3D co-cultures, patient-derived xenografts, and spatial transcriptomics. These efforts could lead to the development of novel diagnostic and therapeutic strategies, ultimately improving outcomes for CRC patients.
In summary, this study provides significant insights into the early metastatic phenotype of CRC, identifying key molecular players and potential biomarkers that contribute to tumour invasion and metastasis. The findings lay the groundwork for future studies aimed at unravelling the complexities of CRC progression and translating these discoveries into clinical applications.
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