While many cancer treatments are improving, cancer remains a major cause of death and suffering, affecting both patients and their families. Increased life expectancy has further increased cancer incidence, putting a heavy burden on society,increasing pressure and healthcare and costs. The objectives of this project are to add fundamental knowledge on how genetic instability is related to ongoing tumor development.
DNA analysis of patient tumors show many different genomic alterations, ranging from point mutations, gene amplifications/losses, to chromosomal rearrangements such as structural variations. Especially gross chromosomal aberrations involving whole chromosomes or are likely to occur during mitosis, a crucial phase in the cell cycle at which the DNA needs to be correctly distributed over both daughter cells.
The fundamental principles of cell division have been studied in different model systems, invaluable in untangling the genetic components, signaling pathways and timing of the components that orchestrate correct cell division. However, to study cell division in a model system that is most representative for human tumors, including 3 dimensional growth and heterogeneity, compatible with high resolution live-cell imaging, we studied patient derived tumor organoids (PDOs). This model allows to study chromosomal instability (CIN), focusing on chromosomal missegregations and mitotic errors during tumor cell proliferation.
Tumors of esophageal origin, such as esophageal adenoma carcinoma’s (EAC) are of specific interest to study the impact of CIN, since EACs seem not driven by sequential acquisition of a specific driver mutations. Rather, EACs progress through multiple combinations of chromosomal alterations, including copy-number changes and large structural variants.
