Oncogenic transformation proceeds through a transient state of cellular plasticity constrained by lineage-specific barriers
5 affiliations
- 1Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 14263
- 2Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 14263
- 3Genomics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 14263
- 4Parse BioSciences, 700 Dexter Ave N Ste 600, Seattle, WA 98109
- 5Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA 14263
Abstract
Normal tissues frequently harbor oncogenic mutations without progressing to cancer, but the cellular basis of this resistance remains poorly defined. We asked whether transformation requires selection of a rare, permissive state within normal-like cell populations. Dermal fibroblasts and mammary epithelial cells responded uniformly to combined HRAS-G12V expression and p53 disruption. Cellular barcoding revealed no loss or enrichment of clones during morphological transformation, arguing against clonal selection as the primary driver of neoplastic reprogramming. Instead, all transduced cells underwent an early, shared transcriptional transition characterized by loss of differentiation markers, induction of RAS-associated and inflammatory programs, activation of alternative-lineage signatures, increased single-cell entropy, and chromatin decondensation. These changes were transient: entropy and chromatin accessibility subsequently declined, and some cells moved toward the control transcriptional state, whereas others stabilized in altered states. The two lineages followed distinct trajectories. Fibroblasts showed greater initial transcriptional plasticity but subsequently reverted more strongly toward the normal state, whereas epithelial cells changed more gradually and continued to diverge from it, suggesting a stronger barrier to transformation in the mesenchymal lineage. Thus, oncogenic perturbation initiated reprogramming throughout the population but did not uniformly produce a stable transformed state. Together, these findings support a model in which normal-like cells tolerate oncogenic mutations not because most cells fail to respond, but because a p53-independent, cell-intrinsic barrier limits the stabilization of malignant transformation following a transient period of heightened plasticity. This framework may facilitate the identification of mechanisms that constrain tumor initiation..
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BibTeX
@misc{frangou2026oncogenic,
title = {{Oncogenic transformation proceeds through a transient state of cellular plasticity constrained by lineage-specific barriers}},
author = {Costakis Frangou and Alfiya Safina and Mairead Commane and Vidula Jahav and Ayah Salameh and Brian Buckley and Prashant Singh and Jesse Luke and Daniel Diaz and Katerina Leonova and Jianmin Wang and Katerina Gurova},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.05.743116},
url = {https://europepmc.org/article/PMC/PMC13729928},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Oncogenic transformation proceeds through a transient state of cellular plasticity constrained by lineage-specific barriers
AU - Costakis Frangou
AU - Alfiya Safina
AU - Mairead Commane
AU - Vidula Jahav
AU - Ayah Salameh
AU - Brian Buckley
AU - Prashant Singh
AU - Jesse Luke
AU - Daniel Diaz
AU - Katerina Leonova
AU - Jianmin Wang
AU - Katerina Gurova
PY - 2026
DA - 2026/08/06
PB - bioRxiv
DO - 10.64898/2026.08.05.743116
UR - https://europepmc.org/article/PMC/PMC13729928
AB - Normal tissues frequently harbor oncogenic mutations without progressing to cancer, but the cellular basis of this resistance remains poorly defined. We asked whether transformation requires selection of a rare, permissive state within normal-like cell populations. Dermal fibroblasts and mammary epithelial cells responded uniformly to combined HRAS-G12V expression and p53 disruption. Cellular barcoding revealed no loss or enrichment of clones during morphological transformation, arguing against clonal selection as the primary driver of neoplastic reprogramming. Instead, all transduced cells underwent an early, shared transcriptional transition characterized by loss of differentiation markers, induction of RAS-associated and inflammatory programs, activation of alternative-lineage signatures, increased single-cell entropy, and chromatin decondensation. These changes were transient: entropy and chromatin accessibility subsequently declined, and some cells moved toward the control transcriptional state, whereas others stabilized in altered states. The two lineages followed distinct trajectories. Fibroblasts showed greater initial transcriptional plasticity but subsequently reverted more strongly toward the normal state, whereas epithelial cells changed more gradually and continued to diverge from it, suggesting a stronger barrier to transformation in the mesenchymal lineage. Thus, oncogenic perturbation initiated reprogramming throughout the population but did not uniformly produce a stable transformed state. Together, these findings support a model in which normal-like cells tolerate oncogenic mutations not because most cells fail to respond, but because a p53-independent, cell-intrinsic barrier limits the stabilization of malignant transformation following a transient period of heightened plasticity. This framework may facilitate the identification of mechanisms that constrain tumor initiation..
SN - 2692-8205
ER -