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Ongoing chromosomal instability in cancer: real-time imaging and single cell genetics of missegregating chromosomes.

Project description

Real-time study of chromosomal instability in cancer

Many genomic aberrations originate from mistakes during cell division, in which the DNA is normally divided equally to both daughter cells. There is a lack of understanding regarding the genetic consequences of mitotic errors for tumourigenesis and genomic instability. Patient-derived tumour organoids and cutting-edge research technologies combining direct microscopic observation of mitosis and single-cell whole-genome sequencing provide an opportunity to study these fundamental questions. The EU-funded OCIC project will study the occurrence and maintenance of genomic instability using organoids derived from esophageal adenocarcinoma (EAC) patients as a model system. The EAC genomes, in particular, show genomic catastrophes that might drive tumourigenesis. Ultimately, the study aims to apply the technology to a panel of human tumour organoids derived from different tissues.

Objective

Genomes from tumor cells are often grossly derailed in DNA content, with chromosomes gained, lost, fused or otherwise rearranged. Presumably, many of these aberrations stem from mistakes during cell division, during which the DNA is normally divided equally to both daughter cells. Cell division is often studied microscopically in 2D cell culture, while DNA sequences from cancer genomes are often re-constructed from tumor patient material. As a consequence, there is still a poor understanding regarding the direct genetic consequences of mitotic errors and as such, genomic instability. Patient-derived tumor organoids, in combination with cutting-edge technology that combines direct microscopic observation of mitotic events, with single-cell whole genome sequencing (scWGS), provide a unique opportunity to tackle these fundamental questions.
To understand the occurrence and maintenance of genomic instability, I will study organoids derived from esophageal adenocarcinoma (EAC) patients. While observed in many cancers, EAC genomes in particular show genomic catastrophes and are thought to drive tumorigenic transformation. Cells will be filmed in real-time to detect mitotic errors. Daughter cells from erroneous divisions will be photoconverted, allowing single cell tracking and isolation for prospective genetic analysis. scWGS will detect imbalances in chromosome number and/or structural rearrangements between the paired daughter cells. Genetic aberrations can be directly linked to the observed mitotic error and cell fate across multiple divisions to understand its role in tumorigenesis.
To couple molecular mechanisms to genetic footprints, fluorescent markers will be implemented to interrogate the type of DNA damage missegregated chromosomes receive, how this affects the subsequent cell cycles, and how this missegregated DNA is re-incorporated into the genome. Finally, I will test these findings across a panel of human tumor organoids derived from different tissues.

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Coordinator

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Net EU contribution
€ 187 572,48
Address
Heidelberglaan 100
3584 CX Utrecht
Netherlands

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Region
West-Nederland Utrecht Utrecht
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00