Microenvironmental Impact on Tumour Cell Phenotype and Genotype in Adult and Paediatric Tumours
(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:
https://lup.lub.lu.se/record/87438dc3-76d8-4a40-bdf6-718b631bfb6e
- author
- Yasui, Hiroaki LU
- supervisor
- opponent
-
- Docent Schlisio, Susanne, Karolinska Institute
- organization
- publishing date
- 2021
- 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}}, keywords = {{cancer genotype; cancer phenotype; malignant rhabdoid tumour; neuroblastoma; ovarian cancer; tumour evolution; Wilms tumour}}, 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/files/86979972/Hiroaki_Yasui_WEBB.pdf}}, year = {{2021}}, }