Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction

Hu, Z.; Majeski, H. E.; Mestre-Farrera, A.; Cai, S.; Lalezarzadeh, A.; Zhang, Y.; Arimoto, K.-I.; Zhang, D.-E.; Piwnica-Worms, H.; Fattet, L.; Yang, J.

doi:10.1101/2025.10.30.681251

bioRxiv · 10.1101/2025.10.30.681251

Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction

Hu, Z.·Majeski, H. E.·Mestre-Farrera, A.·Cai, S.·Lalezarzadeh, A.·Zhang, Y.·Arimoto, K.-I.·Zhang, D.-E.·Piwnica-Worms, H.·Fattet, L.·Yang, J.

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Abstract

Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risk and poor survival. We identify a unique role of the JAK family kinase TYK2 in suppressing breast cancer metastasis under low ECM stiffness. Genetic or pharmacological inhibition of TYK2 in mammary acini and patient-derived organoids leads to invasion at low ECM stiffness by promoting Epithelial-Mesenchymal Transition, which is independent of cytokine-induced JAK/STAT signaling. TYK2 blockade promotes metastasis in breast tumor cell- and patient-derived xenografts. TYK2 localizes at the plasma membrane via IFNAR1 association under low stiffness, but it becomes cytoplasmic and inactivated at high stiffness. Normal human breast epithelium displays membrane-localized TYK2, whereas invasive breast tumors exhibit cytoplasmic TYK2. These findings uncover a TYK2-dependent mechanism by which ECM rigidity suppresses breast cancer metastasis and underscore the need for vigilant breast cancer screening in patients receiving TYK2 inhibitors.

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Hu, Z., Majeski, H. E., Mestre-Farrera, A., Cai, S., Lalezarzadeh, A., Zhang, Y., Arimoto, K.-I., Zhang, D.-E., Piwnica-Worms, H., Fattet, L., Yang, J.. 2025-10-31. Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction. https://doi.org/10.1101/2025.10.30.681251

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