The Downregulated ADAMTS1 Incorporating with A2M Contributes to Tumorigenesis and Alters Tumor Immune Microenvironment in Lung Adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA992476 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC9139094 | biostudies-literature
Project description:Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat’s cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.
2018-01-30 | GSE107194 | GEO
Project description:Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat’s cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumor development. Here we found that A2M modulates tumor cell adhesion, migration and growth by inhibition of tumor promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumor xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumor cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumor promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.
2018-01-25 | GSE106989 | 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: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:The goal of the study was to identify changes in transcriptome expressions upon treatment of A549 cell line samples with activated A2M.
2018-01-23 | GSE106261 | 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.
2025-09-03 | 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: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