Abstract
Protein phase separation has emerged as a crucial mechanism for spatiotemporal regulation of intracellular processes, yet its potential to integrate and compute diverse extracellular signals is not fully understood. Here, we show a mechano-biochemical circuit that harnesses phase separation to process mechanical and biochemical inputs, modulating cell fate decisions. We demonstrate that volumetric compression bidirectionally regulates canonical Wnt/β-catenin signaling, where the presence of Wnt ligands determines the locations of AXIN phase separation to form either LRP6 signalosomes on the cell membrane or β-catenin destruction complexes in the cytosol, while the mechanical stimulus promotes degree of phase separation to amplify either the positive or negative signal. This circuit enhances healthy intestinal organoid proliferation while suppressing patient-derived colorectal cancer organoid growth, revealing its potential for precise mechanotherapy. Our findings establish phase separation as a critical component in mechanical signal transduction and provide a framework for integrating mechanical and biochemical cues in cellular decision-making. This approach opens avenues for targeted therapies and deepens our understanding of how cells process complex environmental information.
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Data availability
The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive in the National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences. Specifically, the single-cell RNA-seq data for human colorectal cancer organoids are accessible in GSA-Human under accession codes HRA015319 and HRA013862, and the bulk RNA-seq data are accessible under accession code HRA013863. The single-cell RNA-seq data for murine organoids are accessible under accession code CRA032833. All unique materials and stable cell lines generated in this study are available from the corresponding author upon reasonable request. All other data supporting the findings of this study are available within the article and its Supplementary Information. Source data are provided with this paper.
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Acknowledgements
We gratefully acknowledge the financial support from the National Key Research and Development Program of China (2024YFF1207300 to Y.L.), the National Natural Science Foundation of China (Grant numbers 32171248 to Y.L., 12472319 to Y.L.), the Fundamental Research Funds for Central Universities, HUST (2021GCRC056 to Y.L.).
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Conceptualization: Y.L.; Methodology: Y.L., J.S., L.W., P.L., F.Q., M.L., L.X., C.S., Y. Zheng, and Y. Zhang; Investigation: J.S., Y.L., X.R., H.X., and W.W.; Visualization: J.S., Y.L., and P.C.; Funding acquisition: Y.L.; Project administration: Y.L.; Supervision: Y.L. and B.F.L.; Writing—original draft: Y.L. and J.S.; Writing—review & editing: Y.L., J.S., and B.F.L.
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Shi, J., Wu, L., Li, P. et al. Volumetric compression regulates the phase separation of AXIN and acts as an operational amplifier to bidirectionally modulate Wnt signaling in organoids. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68209-y
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DOI: https://doi.org/10.1038/s41467-025-68209-y
