Oxidative stress and serum deprivation influence the evolution of newly formed tetraploid cells during tumorigenesis

• 成果类型: Article
• 署名作者: Sweet, Megan L.; Bloomfield, Mathew; Keen, Nicholas; Bano, Nazia; Pan, Xiang; Baudoin, Nicolaas C.; Udayasuryan, Barath; Ahmad, Raffae N.; Riddervold, Eva; Klaiber, Erica; Verbridge, Scott S.; Schmelz, Eva M.; Chen, Jing; Cimini, Daniela
• 署名单位: Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University; Virginia Polytechnic Institute & State University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2522077123
• 发表日期: 2026-06-02
• 页码: e2522077123
• 关键词: centrosome; tetraploidy; WGD; whole genome doubling; oxidative stress; cancer-associated fibroblasts; CENTROSOME AMPLIFICATION; chromosomal instability; macrophages; aneuploidy; promote; duplication; tolerance

摘要

We recently found that newly formed tetraploid (4N) cells in culture quickly lose extra centrosomes after whole genome doubling (WGD). This is inconsistent with the high incidence of centrosome number abnormalities in human cancers and with the observation that 4N cells from mouse tumors carry extra centrosomes, suggesting that centrosome numbers could be affected by certain conditions in the tumor microenvironment (TME). To determine the effect of the TME on the evolution of newly formed 4N cells, we induced WGD in DLD1 colorectal cancer cells and analyzed centrosome and chromosome numbers in mouse tumor samples. We found that the 4N cells displayed a proliferation defect in vivo, that they could enhance the recruitment of stromal cells to the tumor site, and that they were more likely to harbor extra centrosomes compared to 4N cell populations evolved in vitro. Combining a mathematical model that tracks the coevolution of ploidy and centrosome numbers in different cell populations with Bayesian inference, we identified centrosome overduplication as the mechanism underlying the supernumerary centrosome phenotype. Finally, through in vitro evolution experiments, we found that deprivation of growth factors and oxidative stress could explain, respectively, the proliferation defect and the supernumerary centrosomes identified in our in vivo experiments. Overall, our work shows that oxidative stress plays a major role in centrosome overduplication, particularly in 4N cells, suggesting that supernumerary centrosomes and WGD may coexist in certain tumors. Moreover, our findings suggest that the oncogenic effects of WGD could be due, in part, to stromal cell recruitment.