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

Hiroaki Yasui

Research output: ThesisDoctoral Thesis (compilation)

39 Downloads (Pure)

Abstract

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Laboratory Medicine
Supervisors/Advisors
  • Gisselsson Nord, David, Supervisor
  • Karlsson, Jenny, Supervisor
Award date2021 Jan 22
Place of PublicationLund
Publisher
ISBN (Print)978-91-8021-009-6
Publication statusPublished - 2021

Bibliographical note

Defence details
Date: 2021-01-22
Time: 09:00
Place: Nagoya University
External reviewer(s)
Name: Schlisio, Susanne
Title: Docent
Affiliation: Karolinska Institute
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Time: 09:00 in Lund and 17:00 in Nagoya

Subject classification (UKÄ)

  • Obstetrics, Gynecology and Reproductive Medicine

Keywords

  • cancer genotype
  • cancer phenotype
  • malignant rhabdoid tumour
  • neuroblastoma
  • ovarian cancer
  • tumour evolution
  • Wilms tumour

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