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Cited by 18Telomeres, Telomerase, and SenescenceSingle-cell and spatial transcriptomicsGenetics, Aging, and Longevity in Model Organisms

Single-cell RNA sequencing reveals a quiescence-senescence continuum and distinct senotypes following chemotherapy

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Fernandez, Brianna, Passanisi, Victor J., Ashraf, Humza M., Spencer, Sabrina L.·2025·Nature Communications
DOI 10.1038/s41467-025-66836-zPMC PMC12780064

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Abstract

Abstract Quiescence (reversible cell-cycle arrest) and senescence (irreversible arrest) are challenging to distinguish due to a lack of specific biomarkers, yet both arise simultaneously after chemotherapy. While senescence suppresses tumors by limiting proliferation and recruiting the immune system, quiescent cancer cells evade future therapies and may resume proliferation. Here, we pair time-lapse imaging of cell-cycle dynamics with single-cell RNA-sequencing after etoposide treatment to differentiate these states, linking heterogeneous cell-cycle phenotypes to the transcriptomic landscape. We identify diverse senescent types (senotypes) and link them to two arrest pathways – a gradual path arising after a standard mitosis-to-G0 transition, and a rarer but direct path driven by a mitotic slip. Using pseudotime trajectory analysis, we find that senescent phenotypes begin to manifest early and gradually along the first trajectory, even in shallow quiescent cells. These data support a model wherein, following chemotherapy, quiescence and senescence exist on a continuum of cell-cycle withdrawal at a transcriptome-wide level.

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Authors
Fernandez, B., Passanisi, V. J., Ashraf, H. M., & Spencer, S. L.
Affiliations
University of Colorado Boulder (US)
Corresponding author
Spencer, Sabrina L.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-12-23
Volume
17
Issue
1
Pages
169-169
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-66836-z
PMC
PMC12780064
OpenAlex
W7116914533
Cited by
18
References
68
Citations by year
2026: 17 · 2025: 1
FWCI
11.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (1DP2CA238330-01, R01 R01AG082942)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (F31 CA284877)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32 GM142607)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
cellular senescence, quiescence, chemotherapy, etoposide, cell cycle withdrawal, G0 arrest, cancer cells, transcriptomic heterogeneity, pseudotime trajectory analysis, live-cell imaging

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