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

Yasui, Hiroaki LU (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Schlisio, Susanne, Karolinska Institute
organization
publishing date
type
Thesis
publication status
published
subject
keywords
cancer genotype, cancer phenotype, malignant rhabdoid tumour, neuroblastoma, ovarian cancer, tumour evolution, Wilms tumour
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
Doctoral Dissertation Series 2021:3
pages
57 pages
publisher
Lund University, Faculty of Medicine
defense location
Nagoya University
defense date
2021-01-22 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-009-6
language
English
LU publication?
yes
additional info
Time: 09:00 in Lund and 17:00 in Nagoya
id
87438dc3-76d8-4a40-bdf6-718b631bfb6e
date added to LUP
2020-11-10 11:04:32
date last changed
2020-12-10 15:28:22
@phdthesis{87438dc3-76d8-4a40-bdf6-718b631bfb6e,
  abstract     = {This thesis explores how the tumour microenvironment affects the phenotype and shapes the evolution of cancer cells. It encompasses four separate studies:<br/>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.<br/>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.<br/>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.<br/>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.<br/>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.},
  author       = {Yasui, Hiroaki},
  isbn         = {978-91-8021-009-6},
  issn         = {1652-8220},
  language     = {eng},
  number       = {Doctoral Dissertation Series 2021:3},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Microenvironmental Impact on Tumour Cell Phenotype and Genotype in Adult and Paediatric Tumours},
  url          = {https://lup.lub.lu.se/search/ws/files/86979972/Hiroaki_Yasui_WEBB.pdf},
  year         = {2021},
}