Mechanical Force-Induced cGAS Activation in Carcinoma Cells Facilitates Splenocytes into Liver to Drive Metastasis

Abstract

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.