2026-03-31 カリフォルニア大学サンディエゴ校（UCSD）
In healthy tissues, seen in the top two panels here, TYK2 (green) is found on the cell membrane and colocalizes with E-cadherin (red), a protein helps that maintain cellular adhesion and tissue integrity. In tumors, shown in the bottom two panels, TYK2 is spread throughout the cell and no longer colocalizes with E-cadherin. This phenomenon allows cancer cells to more easily spread. Courtesy of UC San Diego Health Sciences.
＜関連情報＞
- https://today.ucsd.edu/story/new-insights-into-breast-cancer-metastasis
- https://www.nature.com/articles/s41467-026-70518-9
細胞外マトリックスの剛性は、TYK2を介したメカノトランスダクションによって乳がんの転移を制御する Extracellular matrix rigidity controls breast cancer metastasis via TYK2-mediated mechanotransduction
Zhimin Hu,Hannah E. Majeski,Aida Mestre-Farrera,Shirong Cai,Arya Lalezarzadeh,Yichi Zhang,Kei-Ichiro Arimoto,Dong-Er Zhang,Helen Piwnica-Worms,Laurent Fattet & Jing Yang
Nature Communications Published:25 March 2026
DOI:https://doi.org/10.1038/s41467-026-70518-9 Unedited version
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.
