PhD defence Ms C. (Charlotte) Henstra

New horizons in colorectal cancer research

Exploring Microbial Metabolites and Tumour Slices

This dissertation explores colorectal cancer (CRC) biology, metastasis, tumour heterogeneity,and therapeutic responses influenced by microbial metabolites. It covers the role of microbialmetabolites in metastasis, the molecular impact of GelE on CRC cells, tumour heterogeneityin Precision-Cut Tumour Slices (PCCTS), ECM remodelling in PCCTS due to GelE, andchemotherapy response in this model.In Chapter 2, a review of bacterial metabolites in CRC metastasis identified GelE, producedby Enterococcus faecalis, as a potential initiator of early metastasis. This highlights gaps inour understanding of microbial involvement in CRC progression and suggests futuretherapeutic targets.Chapter 3 examined the effects of GelE on HCT-116 CRC cells, showing how it influencesthe cell cycle and mobility, contributing to increased invasiveness. This research addressesthe previously underexplored role of GelE in promoting metastasis.In Chapter 4, a protocol for culturing PCCTS was developed to study tumour heterogeneity.The research confirmed the significant variability in CRC tissue and provided strategies toreduce its impact on experimental results, improving study accuracy.Chapter 5 extended the analysis of GelE’s effects using the PCCTS model, focusing on ECMremodelling. The findings highlighted GelE's role in modifying the tumour environment,further implicating it in metastasis.In Chapter 6, the PCCTS model was validated by demonstrating its ability to reflect real-world chemotherapy responses, particularly to FOLFOX-5. The chapter also explored if GelEinfluences chemosensitivity.Overall, this thesis advances CRC research by uncovering the role of GelE in metastasis,tumour heterogeneity, and chemotherapy response. It addresses key knowledge gaps, such asGelE's impact on metastasis and CRC cell behaviour. These insights could guide futurepersonalised cancer treatments and the development of novel therapeutic strategies.