Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer
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ABSTRACT:
PROVIDER: PRJNA1312462 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-09-03 | GSE306824 | GEO
Project description: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.
2025-09-04 | GSE307248 | GEO
Project description:Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer [RNA-Seq]
| PRJNA1314843 | ENA
Project description: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.
2026-03-31 | GSE318870 | GEO
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the PKD1 or PKD2 genes leading to progressive cyst growth and often ESKD. We have previously demonstrated that with loss of Pkd1 the tubules can enlarge without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. Here we compared the transcriptomes from inducible tubule-specific knock out of Pkd1 (PkdTKO) and the uninduced littermate mice kidneys as controls. RNA sequencing revealed significant upregulation of 17 metalloproteinases. Of these, A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1), expressed primarily by the proximal tubule, is the most significantly upregulated following loss of Pkd1 expression. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubule basement membrane (TBM) and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated slower cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. In conclusion, preventing Adamts1 upregulation following loss of tubular Pkd1 expression effectively reduced macrophage accumulation and TBM remodeling, slowing cyst growth and preserving renal function.
2024-09-30 | GSE270531 | GEO
Project description:Expression profiling comparing primary adipocyte progenitor cells from Adamts1 transgenic mice to wild-type littermates
2016-12-06 | GSE71427 | GEO
Project description:Chemoresistance remains a major obstacle to effective colorectal cancer (CRC) treatment. While ferroptosis induction offers promise for chemosensitization, its clinical utility is limited by intrinsic resistance mechanisms. Here, we identify Aurora kinase A (AURKA) as a central ferroptosis suppressor that sustains chemoresistance by rewiring cholesterol metabolism through the SAPS3–AMPK–SREBP2 axis. Mechanistically, AURKA phosphorylates SAPS3 at Ser523/524, promoting its degradation and relieving AMPK suppression. Activated AMPK subsequently inhibits SREBP2 nuclear translocation and DHCR7 transcription, resulting in the accumulation of 7-dehydrocholesterol (7-DHC), a lipid antioxidant that confers ferroptosis resistance. Both genetic and pharmacologic inhibition of AURKA restore ferroptosis sensitivity and enhance chemotherapy efficacy in vitro and in patient-derived xenograft models. Clinically, elevated AURKA expression correlates with poor prognosis and reduced chemotherapy response in CRC patients. These findings define a novel AURKA-driven chemoresistance mechanism, revealing a regulatory nexus between cholesterol homeostasis and ferroptosis evasion, and position AURKA as a promising therapeutic target for chemosensitization in CRC.
2026-03-11 | GSE302491 | GEO
Project description:Adamts1 Promotes Cyst Expansion in Polycystic Kidney Disease
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Project description:Lung cancer is the most dreadful cancer type and has the worst cancer-related clinical outcomes. This study used specimens from the in-house lung cancer cohort and public cohort to verify the roles of downregulated ADAMTS1, a protease remodeling extracellular matrix, to facilitate cancer promotion and progress. Based on the clinical specimens, cell and animal study with the aid of the public databases, we concluded that downregulated expression of ADAMTS1 might promote tumor progression and metastasis and modify the tumor microenvironment in lung cancer. Further investigation would be required for its application in treating lung cancer.
2023-07-12 | GSE236816 | GEO
Project description:This experiment is designed to screen miRNAs that are deregulated during chemoresistance-associated metastasis of lung cancer cells. Chemoresistant metastatic in vivo tumor model of A549-luc-Vector cells was established after four rounds of cisplatin (CDDP) treatments compared to corresponding control solvent treatments. Upon examining profiles of miRNA expression differential between tumor-derived cultured cells from the Ctrl-4th and CDDP-4th treatments, most markedly upregulated and downregulated miRNAs in chemoresistant, metastatic A549-luc-CDDP-4th cells were identified. In order to establish a chemoresistant in vivo tumor model, after inoculation of A549-luc-Vector cells, cisplatin (CDDP) or control solvent was intraperitoneally (i.p.) injected six rounds in a two-week period and cells were isolated from corresponding resultant tumors, cultured and re-transplanted into syngeneic mice to receive the next round of treatment. In our experimental model, human lung cancer xenografts developed chemoresistance in the third round of CDDP treatment (CDDP-3rd) and chemoresistance-associated metastases following the fourth round of treatment. Tumor-derived cultured cells from Ctrl-4th and CDDP (cisplatin)-4th treatment were subjected to miRNA array (Agilent-031181 human miRNA (8*60k) V16.0) analysis, with two biological replications for each treatment.
2015-04-10 | E-GEOD-67727 | biostudies-arrayexpress