Nuclear ADAMTS1 Zymogen Acts as a Transcriptional Coactivator to Drive Chemotherapy-induced Metastasis via Non-canonical cGAS-STING Signaling in Breast Cancer

ABSTRACT: Chemotherapy exerts anti-tumor effects but paradoxically promotes metastasis, a phenomenon whose mechanisms remain incompletely understood. Here, we identify the metalloproteinase ADAMTS1 as a key driver of this process in breast cancer. Although pan-cancer analysis indicates lower ADAMTS1 expression in tumors compared to normal tissues, its elevated expression is associated with poor survival in patients with chemotherapy-treated metastatic breast cancer. Mechanistically, the ADAMTS1 zymogen is imported into the nucleus via importins, where it cooperates with the PBAF complex to activate a set of genes, including TBK1, STING, TRAF6, and MARCHF2, leading to STING ubiquitination and non-canonical cGAS–STING–NF-kB signaling activation, ultimately promoting chemoresistance, metastasis, and cancer stem cell-like malignant properties. Crucially, chemotherapy creates a positive feedback loop: ADAMTS1 is transactivated by NF-kB/p65, while the ADAMTS1-induced E3 ligase MARCHF2 mediates ubiquitin-proteasomal degradation of FURIN, the enzyme required for ADAMTS1 proteolytic maturation. This dual regulation causes nuclear accumulation of the transcriptionally active zymogen. Clinical analyses demonstrate that high ADAMTS1 zymogen expression, rather than its total expression level, strongly correlates with poor patient prognosis. Our results unveil a therapeutically targetable loop whereby chemotherapy-induced, nuclear-localized ADAMTS1 zymogen—rather than the mature metalloenzyme—drives malignant progression. Given that the identified ADAMTS1–cGAS–STING–NF-kB axis can also be activated by PD-1/PD-L1 blockade, targeting this pathway with the ADAMTS1 inhibitor melatonin may mitigate the NF-kB-dependent metastatic risk associated with both chemotherapy and immunotherapy for breast cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318870 | GEO | 2026/03/31

REPOSITORIES: GEO