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bioRxiv · 10.1101/2025.11.06.686987

Cell state plasticity emerging from co-regulated, competitive, and configurable interactions within the AP-1 network

Degefu, Y. N.·Bujnowska, M.·Baumann, D. G.·Fallahi-Sichani, M.
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Abstract

AP-1 transcription factors have been implicated in cellular plasticity, differentiation-state heterogeneity, and phenotype switching in response to cancer therapies. Although AP-1 states, defined by combinatorial expression of AP-1 proteins, are heterogeneous within cell populations, only a subset of possible states is observed. How these states are constrained, why their distributions vary across cell populations, and what drives their phenotypically consequential transitions remain unclear. We develop a mechanistic ODE model of the AP-1 network, capturing dimerization-dependent, co-regulated, and competitive interactions. Calibrated to single-cell protein measurements across diverse melanoma populations and combined with statistical learning, the model reveals network features explaining population-specific AP-1 state distributions. These features correlate with MAPK signaling across tumor lines and individual cells. The model predicts and experiments validate adaptive AP-1 reconfiguration following MAPK inhibition, driving a dedifferentiated, therapy-resistant state that is attenuated through model-guided perturbations. These findings establish AP-1 as a configurable network and provide a quantitative framework for modulating AP-1 driven cell-state plasticity.

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Degefu, Y. N., Bujnowska, M., Baumann, D. G., Fallahi-Sichani, M.. 2025-11-07. Cell state plasticity emerging from co-regulated, competitive, and configurable interactions within the AP-1 network. https://doi.org/10.1101/2025.11.06.686987

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