Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer

Chemoresistance and metastasis are the primary causes of mortality in patients with breast cancer. Here, we demonstrated that the metalloproteinase ADAMTS1 is upregulated in chemotherapy-treated and metastatic breast cancer samples. Mechanistically, the zymogen form of ADAMTS1 undergoes nuclear translocation via importin-dependent transport, where it cooperates with the SWI/SNF complex to activate a set of genes, including TBK1, STING, TRAF6, and MARCHF2, leading to STING ubiquitination and the non-classical cGAS-STING-NF-kB signaling activation, which in turn promotes chemoresistance and metastasis. Notably, long-term chemotherapy establishes a self-reinforcing loop by: (i) NF-kB/p65-mediated transcriptional induction of ADAMTS1, and (ii) MARCHF2-dependent ubiquitin-proteasomal degradation of FURIN, the protease responsible for ADAMTS1 maturation. This dual regulation results in nuclear accumulation of catalytically inactive ADAMTS1 zymogen. Clinical analyses have shown that high ADAMTS1 expression combined with low FURIN expression is strongly associated with poor patient prognosis. These results reveal a key role for the zymogen ADAMTS1 in inducing tumor chemoresistance and metastasis in response to long-term chemotherapy stimulation, supporting the use of its inhibitor melatonin as a therapeutic strategy in combination with chemotherapy for patients with breast cancer. Overall design: we performed cleavage under targets and tagmentation (CUT&Tag) using antibodies against ADAMTS1 in MDA-MB-231BrM cells to profile genome-wide transcriptional targets of ADAMTS1.