Decoding the patterns of clonal dynamics in breast cancer metastasis using single-cell sequencing in patient-derived xenograft models
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Lee, Hakwoo
issued: 2021-05-21T17:10:04Z
issued: 2021
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Introduction: Selection and evolution of tumour cells occurs during cancer progression and metastasis. Understanding the mechanism of clonal dynamics and evolution is an important key to develop new therapeutic strategies for cancer metastasis. This thesis summarizes the development of breast cancer patient-derived xenograft (PDX) metastasis models and measurement of clonal dynamics during metastasis by identifying genomic changes in single cells from primary tumours and metastases. Methods: Tumour cells from untreated primary breast cancer patients were used to develop PDX tumours in immunodeficient mice. Tumours were removed when they reached maximum allowed endpoint size (1,000mm³) during a survival surgery and mice were monitored for metastasis. Immunohistochemical (IHC) staining was performed with 10 markers to characterize tumours. Single cell whole-genome sequencing (scWGS) was used to analyse primary and metastatic tumour cells and copy number alterations (CNAs) were identified which allow us to cluster cells and identify clones. Phylogenetic analysis was performed to identify clonal relationship between primary and metastatic tumour cells. Results: Nine different triple-negative breast cancer PDX lines were tested and 5 developed metastases (SA919, SA535, SA1142, SA605, SA609). We observed that protein marker expression was similar between primary tumour and metastases. Metastatic sites were reproducible over multiple passages in both SA919 and SA535. We also observed that metastatic potential increased with passage number in SA919 while 4 different passages of SA535 showed similar metastases development. From single cell analysis, we observed that the ability to metastasize of primary tumour increases with passage number due to the evolution of clonal population in SA919 and metastatic potential is a property distributed across CNA-defined clones in both SA919 and SA535. We also observed that metastasis to specific anatomical site was not associated with g…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/78403
note: DECODING THE PATTERNS OF CLONAL DYNAMICS IN BREAST CANCER METASTASIS USING SINGLE-CELL SEQUENCING IN PATIENT-DERIVED XENOGRAFT MODELS by Hakwoo Lee MD, Yonsei University, Wonju College of Medicine, South Korea, 2007 M.Sc., Yonsei University, South Korea, 2012 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) May 2021 © Hakwoo Lee, 2021 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: Decoding the patterns of clonal dynamics in breast cancer metastasis using single-cell sequencing in patient-derived xenograft models submitted by Hakwoo Lee in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE in Pathology and Laboratory Medicine Examining Committee: Samuel Aparicio, Pathology and Laboratory Medicine, UBC Supervisor Michael Underhill, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Christian Steidl, Pathology and Laboratory Medicine, UBC Additional Examiner Peter Watson, Pathology and Laboratory Medicine, UBC Additional Examiner Additional Supervisory Committee Members: Will Lockwood, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Poul Sorensen, Pathology and Laboratory Medicine, UBC Supervisory Committee Member iii Abstract Introduction: Selection and evolution of tumour cells occurs during cancer progression and metastasis. Understanding the mechanism of clonal dynamics and evolution is an important key to develop new therapeutic strategies for cancer metastasis. This thesis summarizes the development of breast cancer patient-derived xenograft (PDX) metastasis models and measurement of clonal dynamics during metastasis by identifying genomic changes in single cells from primary tumours and metastases. Methods: Tum…
has type: Thesis/Dissertation
date issued: 2021-11
is shown at: 10.14288/1.0398119
language: eng
degree discipline: Pathology and Laboratory Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Aparicio, Samuel, 1963-
type: Text
identifier URI: http://hdl.handle.net/2429/78403