p53 activity links chromosomal instability to pro-migratory extracellular vesicles
- 1University Medical Center Groningen
Abstract
Chromosomal instability (CIN) promotes tumor evolution and metastasis while imposing cellular stress that can limit cell proliferation via activation of p53 and its downstream effector p21. However, how cells recover from this p53-mediated proliferation block while adopting a more malignant fate remains poorly understood. Here, using a p21-RFP reporter in p53-proficient NIH/3T3 cells, we show that acute CIN gives rise to two phenotypically distinct p21 cell populations with divergent recovery trajectories. p21-RFPLOW cells re-enter the cell cycle following a short cell-cycle arrest, while p21-RFPHIGH cells display a more persistent arrest that coincides with a senescence-like state. Longitudinal transcriptomic and extracellular vesicle (EV) proteomic analyses reveal that extracellular-matrix (ECM)- and adhesion-associated programs are initially suppressed following CIN but specifically reactivated in p21-RFPHIGH cells. The content of late-stage p21-RFPHIGH-derived EVs is enriched for ECM-, adhesion-, and cytoskeleton-associated proteins compared with that of p21-RFPLOW-derived EVs. Consequently, EVs derived from p21-RFPHIGH cells confer increased migration. Together, these findings reveal that CIN can yield distinct p21-expressing cell populations that display different cell-cycle recovery trajectories, EV makeup, and migration-associated paracrine activity.
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BibTeX
@misc{tian2026activity,
title = {{p53 activity links chromosomal instability to pro-migratory extracellular vesicles}},
author = {R. Tian and S. Zheng and L. Zhou and M. Siburian and R. Wardenaar and H. R. de Boer and P. L. Bakker and D. Koot and X. Ling and M. A. T. M. van Vugt and F. Foijer},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.757210},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.757210v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - p53 activity links chromosomal instability to pro-migratory extracellular vesicles
AU - R. Tian
AU - S. Zheng
AU - L. Zhou
AU - M. Siburian
AU - R. Wardenaar
AU - H. R. de Boer
AU - P. L. Bakker
AU - D. Koot
AU - X. Ling
AU - M. A. T. M. van Vugt
AU - F. Foijer
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.757210
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.757210v1
AB - Chromosomal instability (CIN) promotes tumor evolution and metastasis while imposing cellular stress that can limit cell proliferation via activation of p53 and its downstream effector p21. However, how cells recover from this p53-mediated proliferation block while adopting a more malignant fate remains poorly understood. Here, using a p21-RFP reporter in p53-proficient NIH/3T3 cells, we show that acute CIN gives rise to two phenotypically distinct p21 cell populations with divergent recovery trajectories. p21-RFPLOW cells re-enter the cell cycle following a short cell-cycle arrest, while p21-RFPHIGH cells display a more persistent arrest that coincides with a senescence-like state. Longitudinal transcriptomic and extracellular vesicle (EV) proteomic analyses reveal that extracellular-matrix (ECM)- and adhesion-associated programs are initially suppressed following CIN but specifically reactivated in p21-RFPHIGH cells. The content of late-stage p21-RFPHIGH-derived EVs is enriched for ECM-, adhesion-, and cytoskeleton-associated proteins compared with that of p21-RFPLOW-derived EVs. Consequently, EVs derived from p21-RFPHIGH cells confer increased migration. Together, these findings reveal that CIN can yield distinct p21-expressing cell populations that display different cell-cycle recovery trajectories, EV makeup, and migration-associated paracrine activity.
ER -