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

Area of Science:

• Cancer Biology
• Epigenetics
• Systems Biology

Background:

• Drug resistance is a major challenge in cancer therapy, often mediated by cancer cells dedifferentiating into drug-tolerant persister states.
• The early molecular programs driving these reversible cell-state transitions remain poorly understood.

Purpose of the Study:

• To investigate the epigenomic and transcriptomic coordination underlying drug-induced cell dedifferentiation in BRAF-mutant melanoma.
• To identify key molecular drivers and potential therapeutic targets for overcoming drug tolerance.

Main Methods:

• High-temporal-resolution multi-omics profiling of melanoma models and patient samples.
• Information-theoretic approaches and dynamic system modeling to analyze cellular transitions.
• Experimental validation of predicted mechanisms, including NF-κB/RelA pathway involvement.

Main Results:

• Uncovered a hysteretic transition trajectory driven by coupled transcriptional waves and genome-wide chromatin reconfiguration.
• Identified NF-κB/RelA-driven chromatin remodeling as the mechanism for cell-state dedifferentiation.
• Defined a quantitative epigenome gauge for melanoma cell plasticity and identified RelA-target genes involved in the process.

Conclusions:

• Targeting epigenetic machinery can potentiate oncogene inhibition in melanoma.
• NF-κB/RelA activation links oxidative stress to cancer progression and drug tolerance across multiple cancer types.
• The NF-κB axis plays a central role in mediating cancer cell adaptation to therapy.