Microenvironmental Impact on Tumour Cell Phenotype and Genotype in Adult and Paediatric Tumours

Sammanfattning: This thesis explores how the tumour microenvironment affects the phenotype and shapes the evolution of cancer cells. It encompasses four separate studies:First, we explored the effect of chemokines on the peritotumoral microenvironment of ovarian cancer. We found that C-C Motif Chemokine Ligand 2 (CCL2) secreted from mesothelial cells is a dominant chemokine promoting the peritoneal dissemination of ovarian cancer cells.To evaluate the role of tissue differentiation in tumorigenesis, we then focused on Iroquois Homebox B proteins in the childhood kidney cancer Wilms tumour. We showed that these proteins had key roles in normal embryonic kidney development in humans and also had an impact on the differentiation of Wilms tumour cells.In the third and fourth studies, we used multiregional genetic analysis of tumour cells to assess evolutionary trajectories in an environment affected by chemotherapy. In patients with the aggressive childhood cancer malignant rhabdoid tumour we found a pattern of branching evolution across metastatic sites, followed by linear evolution regionally. This resulted in a heterogeneous neoantigen profile and a diverse immune checkpoint status within patients.The fourth study focussed on the childhood cancer neuroblastoma. Here we found two distinct patterns, linear and collateral evolution, coupled to progression and response to chemotherapy, respectively. These patterns were reproduced in a neuroblastoma PDX model and in vitro.Thus, tumour microenvironment has a significant role in shaping tumour cell phenotype and genotype. Finding patterns in these complex interactions may provide future routes to therapy.