Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer

Drug-induced dedifferentiation towards drug-tolerant persister states is a common mechanism cancer cells exploit to escape therapies, hindering durable responses. How early epigenomic and transcriptomic programs coordinate to initiate these reversible transitions remains largely unexplored. Here we employ high-temporal-resolution multi-omics profiling, information-theoretic approaches, and dynamic system modeling to probe these processes in BRAF-mutant melanoma models and patient specimens. We uncover a hysteretic transition trajectory in response to oncogene inhibition and subsequent release, driven by two tightly coupled transcriptional waves that orchestrate genome-scale chromatin reconfiguration. Modeling of these waves suggests NF-κB/RelA-driven chromatin remodeling as the underlying mechanism of cell-state dedifferentiation, which we validate experimentally. We identify RelA-target genes epigenetically modulated to drive this process and define a quantitative epigenome gauge of melanoma cell-state plasticity that supports targeting epigenetic machineries to potentiate oncogene inhibition. Across additional cancer models, oxidative stress-mediated NF-κB/RelA activation emerges as a common driver of transitions into drug-tolerant persister states, revealing a central role for NF-κB axis in coupling oxidative stress to cancer progression.

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Publication Details

Journal
Nature Communications
Published
2026-04-15
DOI
https://doi.org/10.1038/s41467-026-71349-4
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer

Guideng Li, 彭松明, Xiwei Wu, Alphonsus H. C. Ng et al.
Nature Communications
Melanoma and MAPK Pathways
article

Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer

Guideng Li, 彭松明, Xiwei Wu, Alphonsus H. C. Ng, Dazy Johnson, Shiqun Shao, James R. Heath, Guangrong Qin, David Baltimore, Yan Kong, Charles Warden, Yin Tang, Ilya Shmulevich, Raphael Levine, Yapeng Su, J. Lee, Min Xue, Antoni Ribas, Wei Wei, Jinhui Wang, Hanjun Cheng, J Z Guo, Lídia Robert, Qihui Shi, Rachel H. Ng, Victoria Liu, Stephanie Wong, Daniel Chen, Zhuo Wang, Chunmei Liu, Yu Xu, Jie Chen
article en

Abstract

Drug-induced dedifferentiation towards drug-tolerant persister states is a common mechanism cancer cells exploit to escape therapies, hindering durable responses. How early epigenomic and transcriptomic programs coordinate to initiate these reversible transitions remains largely unexplored. Here we employ high-temporal-resolution multi-omics profiling, information-theoretic approaches, and dynamic system modeling to probe these processes in BRAF-mutant melanoma models and patient specimens. We uncover a hysteretic transition trajectory in response to oncogene inhibition and subsequent release, driven by two tightly coupled transcriptional waves that orchestrate genome-scale chromatin reconfiguration. Modeling of these waves suggests NF-κB/RelA-driven chromatin remodeling as the underlying mechanism of cell-state dedifferentiation, which we validate experimentally. We identify RelA-target genes epigenetically modulated to drive this process and define a quantitative epigenome gauge of melanoma cell-state plasticity that supports targeting epigenetic machineries to potentiate oncogene inhibition. Across additional cancer models, oxidative stress-mediated NF-κB/RelA activation emerges as a common driver of transitions into drug-tolerant persister states, revealing a central role for NF-κB axis in coupling oxidative stress to cancer progression.

Nature CommunicationsVol. 17(1)
California Institute of Technology (US), University of California, Los Angeles (US), Shanghai Jiao Tong University (CN), Hebrew University of Jerusalem (IL), Peking University (CN), Fudan University (CN), Institute for Systems Biology (US), Sichuan Agricultural University (CN), Fudan University Shanghai Cancer Center (CN), Peking University Cancer Hospital (CN), Los Angeles Medical Center (US), City of Hope (US), USC Norris Comprehensive Cancer Center (US), UCLA Jonsson Comprehensive Cancer Center
California Institute of Technology, Jean Perkins Foundation, National Natural Science Foundation of China, Sociedad Española de Oncología Médica, National Institutes of Health, National Key Research and Development Program of China, National Cancer Institute
Openalex Percentile: Top 25%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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