Mechanical Force-Induced cGAS Activation in Carcinoma Cells Facilitates Splenocytes into Liver to Drive Metastasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Liver metastasis is the main cause of cancer-related mortality. During the metastasis process, circulating carcinoma cells hardly pass through narrow capillaries, leading to nuclear deformation. However, the effects of nuclear deformation and its underlying mechanisms on metastasis need further study. Here, it is shown that mechanical force-induced nuclear deformation exacerbates liver metastasis by activating the cGAS-STING pathway, which promotes splenocyte infiltration in the liver. Mechanical force results in nuclear deformation and rupture of the nuclear envelope with inevitable DNA leakage. Cytoplasmic DNA triggers the activation of cGAS-STING pathway, enhancing the production of IL6, TNFα, and CCL2. Additionally, splenocyte recruitment by the proinflammatory cytokines support carcinoma cell survival and colonization in the liver. Importantly, both intervening activity of cGAS and blocking of splenocyte migration to the liver efficiently ameliorate liver metastasis. Overall, these findings reveal a mechanism by which mechanical force-induced nuclear deformation exacerbates liver metastasis by regulating splenocyte infiltration into the liver and support targeting cGAS and blocking splenocyte recruitment as candidate therapeutic approaches for liver metastasis. 10.1002/advs.202401127

Inhibition of CDH11 Activates cGAS-STING by Stimulating Branched Chain Amino Acid Catabolism and Mitigates Lung Metastasis of Adenoid Cystic Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Salivary adenoid cystic carcinoma (SACC) is an intractable malignant tumor originates in the secretory glands and frequently metastasizes to the lungs. Hybrid epithelial-mesenchymal transition (EMT) cells within the tumors are correlated with augmented proliferative capacity and facilitation of lung metastasis. Single-cell RNA sequencing and spatial transcriptomic sequencing are employed to reveal the hybrid EMT subsets within the vascular fibroblast microenvironment. These hybrid EMT cells exhibit a pro-tumorigenic impact in vitro. Notably, cadherin 11 (CDH11), a specific marker for hybrid EMT cells, may exert its regulatory role in cellular function by interfering with branched-chain amino acids (BCAA) metabolism by inhibiting branched-chain ketoacid dehydrogenase to activate the mammalian target of the rapamycin pathway, thus making it a potential therapeutic target for SACC. Furthermore, celecoxib and its derivatives are specific CDH11 inhibitors that regulate BCAA metabolism, increase reactive oxygen species production, and subsequently activate the cyclic GMP-AMP synthase-stimulator of the interferongene pathway (cGAS-STING). They also inhibit lung metastasis in NOD-SCID mice in vivo. Overall, these findings suggest a promising treatment strategy that targets hybrid EMT cells to mitigate lung metastasis in SACC. Celecoxib may serve as a promising clinical intervention for the treatment of lung metastases in patients with SACC. 10.1002/advs.202408751