Authors
Degefu, Y. N., Bujnowska, M., Baumann, D. G., Fallahi-Sichani, M.
Abstract
Cell state plasticity drives metastasis and therapy resistance in cancers. In melanoma, these behaviors map onto a melanocytic-to-mesenchymal-like continuum regulated by AP-1 transcription factors. However, how the AP-1 network encodes a limited set of discrete states, why their distributions vary across tumors, and what drives phenotypically consequential AP-1 state transitions remain unclear. We develop a mechanistic ODE model of the AP-1 network capturing their dimerization-controlled, co-regulated, competitive interactions. Calibrated to heterogeneous single-cell data across genetically 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 activity across tumor lines and with variability within clones, linking MAPK signaling to AP-1 states. The model predicts and experiments validate adaptive AP-1 reconfiguration under MAPK inhibition, inducing a dedifferentiated, therapy-resistant state that can be blocked by model-guided AP-1 perturbations. These results establish AP-1 as a configurable network and provide a computational framework for predicting and modulating AP-1 driven cell state plasticity.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 09 Nov 2025.
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