Abstract 4088: Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction

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. Whether and how the soft extracellular matrix (ECM) of normal mammary tissues actively suppresses malignant progression is poorly understood. Here, we identify TYK2 as an essential mechanosensitive metastasis suppressor that preserves epithelial integrity specifically under low ECM stiffness. Using human and mouse basal-subtype mammary acini and multiple triple-negative breast cancer (TNBC) patient-derived organoid models, we show that genetic depletion or pharmacologic inhibition of TYK2 potently induces EMT, disrupts basement membrane, and drives multicellular invasion under soft physiological stiffness. Importantly, this mechanotransduction pathway is independent of canonical interferon/JAK/STAT signaling, as neutralizing type I interferons or inhibiting JAK1/2 or STAT3/5 did not alter stiffness-dependent EMT and invasion. Mechanistically, TYK2 localizes to the plasma membrane via IFNAR1 binding under low stiffness, which retains the EMT transcription factor TWIST1 in the cytoplasm. Increasing ECM stiffness causes TYK2 to disperse into the cytoplasm, leading to nuclear translocation of TWIST1 and EMT activation. In vivo, TYK2 knockdown or systemic inhibition with the clinical TYK2 inhibitor deucravacitinib markedly increased local invasion and significantly enhanced lung metastasis in MCF10DCIS and TNBC patient-derived xenografts, while leaving primary tumor growth unchanged. Supporting a mechanosensory role of TYK2, normal human breast epithelium exhibited strong membrane-localized TYK2, whereas invasive breast cancers displayed diffuse cytoplasmic TYK2, mirroring the high-stiffness phenotype observed in vitro. These findings uncover TYK2 as a ECM rigidity-dependent epithelial safeguard that actively suppresses EMT and metastatic progression in basal-subtype breast cancer. By demonstrating that TYK2 blockade or loss unleashes invasion and metastasis in multiple xenograft and patient-derived TNBC models and that normal breast epithelium relies on membrane-anchored TYK2 for mechanotrasnduction, this work reveals a fundamental stiffness-governed epithelial defense mechanism. Given the increasing clinical use of TYK2 inhibitors for autoimmune diseases, these results raise important considerations for patient monitoring and metastasis risk. Citation Format: Zhimin Hu, Hannah Elisabeth Majeski, Aida Mestre-Farrera, Shirong Cai, Arya Lalezarzadeh, Yichi Zhang, Kei-Ichiro Arimoto, Dong-Er Zhang, Helen M. Piwnica-Worms, Laurent Fattet, Jing Yang. Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4088.