The role of telomere-related tetraploidization in cancer

端粒相关四倍体化在癌症中的作用

基本信息

批准号：
8161963
负责人：
Titia de Lange
金额：
$ 35.17万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8161963
关键词：
Actins Address Anchorage-Independent Growth Aneuploidy Automobile Driving Biological Models Cell Line Cell Nucleus Cell division Cell fusion Cells Centrosome Chromosome abnormality Chromosomes Complement Cytokinesis DNA Damage Data Development Diagnostic Neoplasm Staging Dicentric chromosome Diploidy Epithelial Cells Fibroblasts Frequencies Functional disorder Geminin Genetic Genomic Instability Human In Vitro Knowledge Lead Length Life Malignant - descriptor Malignant Neoplasms Mammary gland Mediating Mitosis Mitotic Modeling Monitor Mus Nude Mice Oncogenes Pancreas Pathway interactions Phosphotransferases Ploidies Proliferating Proteins Protocols documentation Recording of previous events Research Retinal Role S Phase Signal Transduction Solid Neoplasm Squamous Cell Staging System Telomerase Telomere Shortening Testing Tetraploidy Transgenes Tumorigenicity Work Zeocin base cell type cellular imaging chromosome loss design dimethylbenzanthracene drug sensitivity experience falls genome-wide improved in vivo indexing keratinocyte mouse model novel precursor cell research study response restoration telomere tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): This project addresses a key problem in human cancer: the origins of aneuploidy. Aneuploidy is among the hallmarks of human solid tumors and is now recognized as one of the contributing factors in malignant transformation but its origin is not fully understood. While sporadic gains and losses of chromosomes can adequately explain a substantial fraction of the aberrant chromosome numbers, this explanation falls short in the context of cancers with a triploid or near-tetraploid chromosome number. It has been proposed that cancers carrying a high chromosome number originate from an unstable tetraploid intermediate. Tetraploid cells are known to mis-segregate chromosomes at a high rate, generating subclones with the sub-tetraploid or near-triploid chromosome numbers observed in cancer. These considerations have led to a quest to understand the mechanism by which tetraploidy arises during tumorigenesis. Prior to our work, three main mechanisms had been proposed. First, tetraploid cells can arise from (virally-mediated) cell-cell fusion, yielding a bi-nucleated cell which is converted into a tetraploid state during the next cell division. Second, tetraploidy can arise when cells experience a prolonged arrest in mitosis. Depending on the genetic context, mitotic slippage can occur, yielding a cell with a single tetraploid nucleus and two centrosomes in G1. Third, when the cleavage furrow is impeded, either experimentally (actin inhibition) or by a lagging chromosome, cytokinesis fails and tetraploidy arises. While each of these pathways may be operational in some cancers, they are unlikely to be a general aspect of tumorigenesis and do not explain the high frequency of tetraploidization suggested by the large percentage of tumors with a high chromosome number. Based on our preliminary data, we propose a novel mechanism for tetraploidization that involves the DNA damage signal originating from shortened dysfunctional telomeres. It has long been known that most human solid tumors experience a period of telomere shortening before telomerase is upregulated. We propose that the resulting telomere dysfunction generates a DNA damage response that can induce tetraploidization as well as other forms of genome instability, such as the Breakage-Fusion Bridge cycles resulting from dicentric chromosomes. This hypothesis is attractive because it can explain the generality and high frequency of tetraploidization in solid tumors. In addition, the insult driving tetraploidization - telomere dysfunction - is a transient state. The current project is designed to test this new hypothesis. Given the large number of tumors showing evidence of past tetraploidization, our work has the potential to have broad impact on the knowledge of the origins of aneuploidy in cancer. PUBLIC HEALTH RELEVANCE: Most human solid tumors often show aberrant chromosome numbers, a phenomenon referred to as aneuploidy. Aneuploidy is an important factor in the formation of human cancer but it is not understood how aneuploidy arises. This project tests a new hypothesis on the origin of aneuploidy.