Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Wang, Kai; Xuan, Zixue; Liu, Xiaoyan; Zheng, Mei‐Ling; Yang, Chao

doi:10.3389/fimmu.2022.1059376

Cited by 11 publications

(11 citation statements)

References 278 publications

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“…The role of ADAMs in chemotherapy resistance has been described earlier for other entities such as cervical cancer, liver cancer, colorectal cancer and bladder cancer [5–8, 10, 46]. In line with our previous studies focussing on chemoresistance in ovarian cancer [5–7], we showed strong combinatorial effects of ADAM17 inhibition and cisplatin treatment in cervical cancer.…”

Section: Discussionsupporting

confidence: 89%

“…Clinical studies focussing on ADAM17 inhibition often suffer from high toxicity and high structural homology of the catalytic domains of ADAM-family members. Recently the focus has shifted on the non-catalytic domains that appear to be more promising [46, 57]. Therefore, our individualised organoid systems, complemented with our newly developed automated readout tools to predict treatment responses, would present an important tool to foster personalised therapy in cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

Holthaus,

Rogmans,

Gursinski

et al. 2024

Preprint

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Background: Cervical cancer represents one of the main causes of female, cancer-related mortality worldwide. The majority of cancers are caused by human papillomaviruses such as HPV16 and HPV18. As chemotherapeutic resistance to first-line platinum treatment is still a predominant clinical challenge in advanced cervical cancer, novel treatment options including combinatorial therapies are urgently required to overcome chemotherapeutic resistance. Inhibition of A Disintegrin And Metalloproteinase (ADAM)-family members, heavily involved in tumour progression of a vast range of solid tumours, strongly improved response to chemotherapeutic treatment in other tumour entities including ovarian cancer. Methods: We established two- and three-dimensional models derived from three traditional cervical cancer cell lines and ectocervical cancer-derived organoids. Following characterisation, these models were used to investigate their response to cisplatin treatment in the absence and presence of ADAM inhibitors using viability assays and automated live cell imaging. Results: The pivotal role of the metalloprotease ADAM17 driving chemotherapy resistance was detectable in all ectocervical cultures irrespective of the model system used, whereas ADAM10 inhibition was predominantly effective only in loosely aggregated spheroids. We showed prominent differences regarding treatment responses between 2D monolayers compared to 3D spheroid and 3D organoid model systems. Particularly, the organoid system, regarded as the closest representation of primary tumours, exhibited reliably the combinatorial effect of ADAM17 inhibition and cisplatin in all three individual donors. Conclusions: As two- and three-dimensional models of the same cell lines differ in their responses to chemotherapy it is essential to validate treatment strategies in more advanced model systems representing the patient situation more realistically. Ectocervical organoids showed reliable results regarding treatment responses closely mimicking the primary tumours and could therefore serve as an important tool for personalized medicine in cervical cancer. These findings strengthen the role of ADAM17 as a potential novel target for combinatorial treatments to overcome chemoresistance in cervical cancer.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

Holthaus,

Rogmans,

Gursinski

et al. 2024

Preprint

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“…Amongst the 21 ADAMs identified in the human genome, only 13 are actually proteolytically active while the rest lack the required Zn-binding motif in the catalytic domain [ 121 , 122 , 123 ]. Two closely related members of this family, ADAM10 and ADAM17, are crucial cell surface enzymes responsible for the cleavage and release of the ectodomains from a large variety of cell surface substrates, a process known as “ectodomain shedding”, which plays an essential role in numerous processes, including development, inflammation, and cancer [ 124 , 125 ]. ADAM10 and ADAM17 are atypical members of the ADAM family because the extracellular cysteine-rich and EGF-like domains are in these two members replaced by a unique membrane proximal domain (MPD), that is involved both in substrate recognition and regulation of their sheddase activity [ 86 , 126 ].…”

Section: The Dual Role Of Adam17 and Adam10 Metalloproteinases In The...mentioning

confidence: 99%

Molecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer

Clares-Pedrero,

Rocha-Mulero,

Palma-Cobo

et al. 2024

IJMS

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Extracellular vesicles produced by tumor cells (TEVs) influence all stages of cancer development and spread, including tumorigenesis, cancer progression, and metastasis. TEVs can trigger profound phenotypic and functional changes in target cells through three main general mechanisms: (i) docking of TEVs on target cells and triggering of intra-cellular signaling; (ii) fusion of TEVs and target cell membranes with release of TEVs molecular cargo in the cytoplasm of recipient cell; and (iii) uptake of TEVs by recipient cells. Though the overall tumor-promoting effects of TEVs as well as the general mechanisms involved in TEVs interactions with, and uptake by, recipient cells are relatively well established, current knowledge about the molecular determinants that mediate the docking and uptake of tumor-derived EVs by specific target cells is still rather deficient. These molecular determinants dictate the cell and organ tropism of TEVs and ultimately control the specificity of TEVs-promoted metastases. Here, we will review current knowledge on selected specific molecules that mediate the tropism of TEVs towards specific target cells and organs, including the integrins, ICAM-1 Inter-Cellular Adhesion Molecule), ALCAM (Activated Leukocyte Cell Adhesion Molecule), CD44, the metalloproteinases ADAM17 (A Disintegrin And Metalloproteinase member 17) and ADAM10 (A Disintegrin And Metalloproteinase member 10), and the tetraspanin CD9.

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“…Among the 64 putative c-Fos targets in OIR P14 rod photoreceptor cells, a gene named a disintegrin and metalloprotease 17 (Adam17), also called tumor necrosis factoralpha-converting enzyme (TACE) is a shedding protease responsible for inflammation and angiogenesis [49]. Our genome browser analysis of CUT&Tag tracks revealed a c-Fos peak that precisely overlapped with H3K27ac and H3K4me3 peaks at the TSS of the Adam17 gene, while no such overlap with H3K27me3 peaks was observed at the TSS of Adam17 gene (Fig.…”

Section: C-fos Was Both Induced and Activated In The Photoreceptor La...mentioning

confidence: 99%

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

Wang,

Kaneko

et al. 2024

Angiogenesis

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Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

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Immunomodulatory role of metalloproteinase ADAM17 in tumor development

Cited by 11 publications

References 278 publications

Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

Inhibition of ADAM17 increases cytotoxic effect of cisplatin in cervical spheroids and organoids

Molecular Determinants Involved in the Docking and Uptake of Tumor-Derived Extracellular Vesicles: Implications in Cancer

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

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