Abstract 2048: Property analysis of chromosomal instability-adapted cells using multi-omics approaches

Abstract

Abstract Background: Chromosomal instability (CIN), which includes polyploidy and aneuploidy, is characterized as the pillar of cancer hallmarks. CIN is observed in >90% solid tumors, being correlated with malignancy grades, poor prognosis, and drug resistance. However, it is still unclear yet how aneuploidy triggers cancer initiation/progression, or how aneuploidy gives negative impacts on cancer therapeutics. In this study, we established our original CIN cell line model, aiming to understand biological significance of cancer aneuploidy on the CIN-mediated stress adaptation.Method: A colorectal cancer cell, HCT116, was treated with an Aurora-B kinase inhibitor for 24 hours to transiently induce CIN in these cells, and then cultured in a drug-free medium for >10 days to establish “CIN-adapted cells”. Cell growth was evaluated by intracellular ATP concentrations. RNAs and DNAs extracted from the cells were subjected to RNA-seq, Exome-seq, and ATAC-seq by the NovaSeq sequencing systems. The cell lysates were subjected to metabolomics analyses by GC-MS system. Bioinformatics analyses were performed using these multiple-omics data.Results: In 10 days after aneuploid formation, 90% aneuploid cells were killed, while 10% aneuploid cells were proliferative with a high growth rate equivalent to that of the parental euploid cells, which appeared to overcome the CIN-mediated antiproliferative pressure. The CIN-adapted cells revealed to be highly sensitive to the low-glucose and hypoxic condition, suggesting that the metabolic pathways would be modulated to adjust the cells to the aneuploid-mediated stress. Transcriptome and metabolome analyses also revealed the gene expressions and the metabolites for the lipid or amino acids metabolisms were significantly changed in the CIN-adapted cells. These findings suggest that the CIN-adapted cells appear to restructure their signaling networks of the lipid and amino acid metabolic pathways, which is expected to play important roles for the aneuploid cells to survive under the CIN-mediated stress. We perform drug screening to identify essential factors in the process leading to CIN-adapted, aiming for a comprehensive understanding of the molecular mechanism and signal networks.Conclusions: We comprehensively characterized the CIN-adapted cancer cell model by the multi-omics approaches. These findings will help us to deeply understand the biological significance of CIN in cancer cells, providing a new insight to novel cancer therapeutics targeting CIN. Citation Format: Tomoko Yamamori Morita, Hiroshi Haeno, Hideki Makinoshima, Ayako Suzuki, Susumu S. Kobayashi, Akihiro Ohashi. Property analysis of chromosomal instability-adapted cells using multi-omics approaches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2048.