2026-05-25 バージニア工科大学（Virginia Tech）
＜関連情報＞
- https://news.vt.edu/articles/2026/05/science-cancer-progression.html
- https://www.pnas.org/doi/full/10.1073/pnas.2522077123
- https://aacrjournals.org/cancerres/article/86/9/2126/784012/Cell-and-Nuclear-Size-Is-Associated-with
酸化ストレスと血清欠乏は、腫瘍形成過程における新たに形成された四倍体細胞の進化に影響を与える Oxidative stress and serum deprivation influence the evolution of newly formed tetraploid cells during tumorigenesis
Megan L. Sweet, Mathew Bloomfield, Nicholas Keen, +10 , and Daniela Cimini
Proceedings of the National Academy of Sciences Published:May 26, 2026
DOI:https://doi.org/10.1073/pnas.2522077123
Significance
Understanding the mechanism that links whole genome doubling (WGD), extra centrosomes, and tumorigenesis to one another is crucial to understanding tumor progression, as many human tumors have a high incidence of WGD and extra centrosomes. Using in vivo and in vitro approaches, we find that newly formed tetraploid (4N) cells have a proliferative disadvantage, due to low nutrient availability. However, a small population of 4N cells is sufficient to promote the recruitment of protumorigenic stromal cells. Moreover, 4N cells are more likely to undergo centrosome overduplication in vivo, which could be driven by an increase in reactive oxygen species common in the tumor microenvironment (TME). Taken together, our work expands how WGD, extra centrosomes, and the TME can promote tumorigenesis.
Abstract
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.
細胞および核のサイズは、全ゲノム倍加を起こす癌細胞における染色体不安定性および腫瘍形成能と関連している Cell and Nuclear Size Is Associated with Chromosomal Instability and Tumorigenicity in Cancer Cells That Undergo Whole Genome Doubling
Mathew Bloomfield;Sydney M. Huth;Daniella S. McCausland;Ron Saad;Nazia Bano;Tran N. Chau;Megan L. Sweet;Nicolaas C. Baudoin;Andrew McCaffrey;Kai Fluet;Eva M. Schmelz;Uri Ben-David;Daniela Cimini
Cancer Research Published:May 04 2026
DOI:https://doi.org/10.1158/0008-5472.CAN-24-3718
Abstract
Whole genome doubling (WGD) is a frequent event in cancer evolution associated with chromosomal instability, metastasis, and poor prognosis. Whereas the genomic consequences of WGD are well documented, nongenetic alterations that accompany WGD, such as changes to cell and nuclear size, may also play an important role in tetraploid (4N) cancer cell physiology. In this study, we showed that cell and nuclear volume does not always scale with DNA content after WGD in cancer cells, resulting in 4N cells that differ in size. Small size was associated with enhanced cell fitness, mitotic fidelity, and tumorigenicity in 4N cancer cells and with poor patient survival in WGD-positive human cancers. Overall, these results suggest that cell and nuclear size may contribute to the tumorigenic potential of 4N cancer cells and could be an important prognostic marker in human tumors that undergo WGD.
Significance:
Cancer cell size varies after whole genome duplication, with smaller cells exhibiting high tumorigenicity and correlating with poor patient survival, demonstrating the clinical relevance and highlighting the biomarker potential of cell size.
