Abstract
Mechanical cues from the extracellular matrix (ECM) regulate various cellular processes. In breast cancer, increased tumor stiffness is associated with elevated metastasis risks and poor survival. Here we report 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 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 ECM stiffness, whereas high rigidity causes TYK2 cytoplasmic mislocalization and inactivation. Consistently, normal 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 breast cancer screening in patients receiving TYK2 inhibitors.
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Acknowledgements
We thank Dr. Tony Hunter and other members of the Yang lab for technical advice and helpful discussions. We thank the La Jolla Institute microscopy core, in particular Z. Mikulski for SHG imaging. We thank the UCSD Shared Microscope Facility and UCSD Cancer Center Support Grant P30 CA23100 from NCI. We thank Dr. Serge Y. Fuchs at Univ. of Pennsylvania for the human IFNAR1 construct and Dr. Oluwale Fadare at UCSD for human normal breast tissue slides. This work was supported by grants from NCI (R01CA174869, RO1CA262794, R01CA268179, and R01CA236386), the 2021 AACR-Bayer Innovation and Discovery Grant 21-80-44-YANG, The St. Baldrick’s Foundation Research Grant, and Krueger v. Wyeth research award to J.Y. PDX models were established through a generous gift from the Cazalot family and from funds from the MD Anderson Cancer Center Breast Cancer Moon Shot Program. Additional funding sources that supported this work include the Cancer Prevention and Research Institute of Texas RP150148 and RP160710 (to H.P.-W.). H.P.-W. is an ACS Research Professor. Z. H. was supported by a Pfizer Oncology-Cell Signaling San Diego Postdoctoral Fellowship. H.S.M. was supported by NIH Pre-doctoral Training grant T32GM007752 and by a predoctoral NRSA fellowship from NCI (F31CA213800). L.F. was supported by an AACR Basic Cancer Research fellowship. A.M.F. was supported by TRDRP Postdoctoral Award T32FT4922.
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Conceptualization: Z.H., H.S.M, and J.Y.; Methodology: Z.H., H.S.M, A.M.F., L.F.; Investigation: Z.H., H.S.M, A.M.F., L.F., S.C. Y.Z. and A.L.; Writing–Original Draft: Z.H., H.S.M., and J.Y.; Writing–Review and Editing: L.F., J.Y., H.P.-W. and D.-E. Z.; Funding Acquisition: Z.H., H.S.M, A.M.F., L.F., J.Y. and H.P.-W; Resources: S.C., S.D., H.P.-W, and K.-I. A.; Supervision: J.Y.
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Hu, Z., Majeski, H.E., Mestre-Farrera, A. et al. Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70518-9
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DOI: https://doi.org/10.1038/s41467-026-70518-9
