Development of patient-derived models to study tumor heterogeneity Studies of colorectal cancer

Tumor heterogeneity can be classified into two categories: intra- and inter-tumor heterogeneity. While tumor intra-heterogeneity marks the heterogeneity observed between different types of cells within a tumor, tumor inter- heterogeneity marks the heterogeneity that exists across different patient’s tumors. The work described in the thesis is a minute contribution providing more insight of these tumor heterogeneities and hopefully paving the way towards an effective personalised colorectal care regimen.
In this thesis, we discuss how cancer stem cells (CSCs) contribute to tumor intra- heterogeneities. We describe the method to culture them and identify their presence with markers used to define healthy intestinal stem cells. We will also demonstrate how other tumor components are able to steer the tumor’s malignant properties. We further approach the tumor inter-heterogeneity with studying the multiple subtypes present in CRC that are characterised with distinct biological pathways and clinical outcomes. Science is just at the beginning of learning the biology underlying the difference between the subtypes with the aim of identifying the best therapy option for each subtype. Exploring therapy based on subtype might pose a realistic approach in personalised medicine because the clinical reality has not yet approached the stage where drugs can be selected specifically for each patient. To this end, appropriate pre-clinical models representing the distinct subtypes need to be developed and characterised. In this thesis, the different subtypes found in patients were studied to determine whether they could be modelled through primary cultures and patient-derived xenograft (PDX) models.