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Nuclear morphology predicts cell survival to cisplatin chemotherapy

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Title
Nuclear morphology predicts cell survival to cisplatin chemotherapy
Author(s)
Kim, C.-J.; Gonye, A.L.; Truskowski, K.; Lee, C.-F.; Yoon-Kyoung Cho; Austin, R.H.; Pienta, K.J.; Amend, S.R.
Publication Date
2023-08
Journal
Neoplasia (United States), v.42
Publisher
Elsevier Inc.
Abstract
The emergence of chemotherapy resistance drives cancer lethality in cancer patients, with treatment initially reducing overall tumor burden followed by resistant recurrent disease. While molecular mechanisms underlying resistance phenotypes have been explored, less is known about the cell biological characteristics of cancer cells that survive to eventually seed the recurrence. To identify the unique phenotypic characteristics associated with survival upon chemotherapy exposure, we characterized nuclear morphology and function as prostate cancer cells recovered following cisplatin treatment. Cells that survived in the days and weeks after treatment and resisted therapy-induced cell death showed increasing cell size and nuclear size, enabled by continuous endocycling resulting in repeated whole genome doubling. We further found that cells that survive after therapy release were predominantly mononucleated and likely employ more efficient DNA damage repair. Finally, we show that surviving cancer cells exhibit a distinct nucleolar phenotype and increased rRNA levels. These data support a paradigm where soon after therapy release, the treated population mostly contains cells with a high level of widespread and catastrophic DNA damage that leads to apoptosis, while the minority of cells that have successful DDR are more likely to access a pro-survival state. These findings are consistent with accession of the polyaneuploid cancer cell (PACC) state, a recently described mechanism of therapy resistance and tumor recurrence. Our findings demonstrate the fate of cancer cells following cisplatin treatment and define key cell phenotypic characteristics of the PACC state. This work is essential for understanding and, ultimately, targeting cancer resistance and recurrence. © 2023
URI
https://pr.ibs.re.kr/handle/8788114/13433
DOI
10.1016/j.neo.2023.100906
ISSN
1522-8002
Appears in Collections:
Center for Soft and Living Matter(첨단연성물질 연구단) > 1. Journal Papers (저널논문)
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