Role of whole genome duplication in chromosomal instability

Authors

• O Gonul Geyik
• D Wangsa
• Z Yuce
• T Ried

Abstract

Aneuploidy and chromosome instability (CIN) are hallmarks of cancer but their impact and evolution in cancer is still unclear. Tumor cells compete for survival in their microenvironment with continuously changing conditions causing more aggressive subpopulations with different mutations and/or epigenetic alterations to arise and proliferate in the tumor population which results in intratumoral heterogeneity (ITH). Whole genome duplication (WGD) is related to higher degrees of genomic instability, ITH and increased migratory capabilities in colorectal cancer. In order to study the role of WGD in progression of cancer, we used FACS sorted isogenic DLD-1 diploid and tetraploid cells to determine the consequence of WGD to chemotherapeutics (5-Fluorouracil, Oxaliplatin, Irinotecan, Paclitaxel, and Gemcitabine) and environmental stress (hypoxia). We also labeled two diploid and three tetraploid clones with different fluorescence colors in order to better assess whether 4N clones that have undergone WGD have an advantage which allows them to outcompete their 2N counterparts. Fluorescent 2N and 4N cells, sorted at the NCI FACS Core Facility, were mixed in equal proportions to generate an in vitro model to study tumor population kinetics. We evaluated the response to chemotherapeutic drugs and hypoxia using cell viability, colony formation and invasion assays. Our results indicate that 4N clones have a higher tolerance to chemotherapeutic drugs. The outcome of this study will shed light on the mechanism that underlies therapy resistance and how WGD evolves in cancer.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021