Abstract
Revealing the lineage relations among cancer cells can shed light on tumor growth patterns and metastasis formation, yet cell lineages have been difficult to come by in the absence of a suitable method. We previously developed a method for reconstructing cell lineage trees from genomic variability caused by somatic mutations. Here, we apply the method to cancer and reconstruct, for the first time, a lineage tree of neoplastic and adjacent normal cells obtained by laser microdissection from tissue sections of a mouse lymphoma. Analysis of the reconstructed tree reveals that the tumor initiated from a single founder cell, approximately 5 months before diagnosis, that the tumor grew in a physically coherent manner, and that the average number of cell divisions accumulated in cancerous cells was almost twice than in adjacent normal lung epithelial cells but slightly less than the expected figure for normal B lymphocytes. The cells were also genotyped at the TP53 locus, and neoplastic cells were found to share a common mutation, which was most likely present in a heterozygous state. Our work shows that the ability to obtain data regarding the physical appearance, precise anatomic position, genotypic profile, and lineage position of single cells may be useful for investigating cancer development, progression, and interaction with the microenvironment.
Highlights
Despite several decades of scientific research, basic properties of the growth and spread of tumor cells remain controversial [1]
Analysis of 37 single cancer and adjacent normal cells was sufficient to establish the monoclonal origin of the tumor cells, calculate depth of cancerous cells and normal lung epithelium cells, calculate the www.aacrjournals.org age of the tumor, characterize the growth pattern of the tumor, and to detect the presence of a TP53 mutation in cancer cells in the heterozygous state
All tumor cells are clustered on a single subtree, indicating a monoclonal origin, and this result is in line with the classic model of tumorigenesis
Summary
Despite several decades of scientific research, basic properties of the growth and spread of tumor cells remain controversial [1]. This may seem surprising because cancer is primarily a disturbance of cell growth and survival, and an aberrant growth pattern is perhaps the only property that is shared by all cancers. Because the initiation and much of the subsequent development of tumors occurs before diagnosis, studying the growth and spread of tumors seems to require retrospective techniques, and these have not been forthcoming. In the last several years, quantitative analysis of somatic genetic mutations has emerged as a powerful research tool, which is. Shapiro is the Incumbent of The Harry Weinrebe Professorial Chair of Computer Science and Biology and of The France Telecom-Orange Excellence Chair for Interdisciplinary Studies of the Paris ‘‘Centre de Recherche Interdisciplinaire.’’
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