The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling

Mierke, Claudia Tanja

doi:10.3389/fcell.2023.1130823

Cited by 8 publications

(4 citation statements)

References 160 publications

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“…ADAM8 has been reported to be highly expressed in pancreas cancer ( Schlomann et al, 2015 ; Yu et al, 2020 ) or ductal adenocarcinoma ( Jaworek et al, 2021 ), is coupled to poor clinical prognosis of cancer and seems to be linked to the effect of chemoresistance to medical treatment of cancers ( Conrad et al, 2019 ). Based on all these findings, it can be assumed that ADAM8 plays a role in cancer cell migration, such as breast cancer cell migration ( Mierke, 2023 ). Therefore, we revealed that the motility of ADAM8 knock down MDA-MB-231 human breast cancer cells and ADAM8-Ctrl MDA-MB-231 cells in 3D collagen matrix scaffolds is altered.…”

Section: Discussionmentioning

confidence: 99%

The role of ADAM8 in the mechanophenotype of MDA-MB-231 breast cancer cells in 3D extracellular matrices

Hayn

Fischer

Mierke

2023

Front. Cell Dev. Biol.

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The majority of investigations of cancer cells have been performed in an oversimplified 2D in vitro environment. In the last decade there is a trend toward more sophisticated 3D in vitro cell culture model systems that can bridge the existing gap between 2D in vitro and in vivo experiments in the field of biophysical and cell biological cancer cell research. Here, we hypothesize that the bidirectional interplay between breast cancer cells and their tumor microenvironment is critical for the outcome of the disease. Thereby, the tissue remodeling processes evoked by cancer cells are important for cancer cell-driven mechanical probing of their matrix environment and on cancer cell adhesion and motility. When remodeling processes have been explored, the emphasis was placed on matrix metalloproteinases and rather not on a disintegrin and metalloproteases (ADAMs). However, the role of ADAM8 in cell mechanics regulating cellular motility in 3D collagen matrices is still unclear. Thus, in this study, we focus on the function of ADAM8 in matrix remodeling and migration of 3D extracellular matrix scaffolds. Therefore, human MDA-MB-231 breast carcinoma cells with ADAM8 knocked down, referred to as ADAM8-KD cells, as well as MDA-MB-231 scrambled control cells, referred to as ADAM8-Ctrl cells, have been used to examine their ability to interact with and migrate in dense extracellular 3D matrices. The fiber displacements, as the capacity of cells to deform the environmental 3D matrix scaffold, has been observed. ADAM8-KD cells displace collagen fibers more strongly than ADAM8-Ctrl cells. Moreover, ADAM8-KD cells migrated more numerous in 3D collagen matrices compared to ADAM8-Ctrl cells. The impairment of ADAM8 using the ADAM8 inhibitor BK-1361 led to significantly increased fiber displacements of ADAM8-Ctrl cells to the levels of ADAM8-KD cells. In contrast, the inhibitor had no effect on ADAM8-KD cells in terms of fiber displacements as well as on the quantitative characteristics of cell invasion of ADAM8-Ctrl cells, albeit the cells that were found in the matrix invaded considerably deeper. When matrix remodeling by cells is impaired through GM6001, a broad-band metalloproteinase inhibitor, the fiber displacements of both cell types increased. In fact, ADAM8 is known to degrade fibronectin in a direct and/or indirect manner. The supplementation of fibronectin before polymerization of the 3D collagen matrices caused an enhancement in fiber displacements as well as in cell invasion into fibronectin-collagen matrices of ADAM8-Ctrl cells, whereas the fiber displacements of ADAM8-KD cells did not change. However, fibrinogen and laminin supplementation induced an increase in fiber displacements of both cell types. Thus, the impact of fibronectin on selective increase in fiber displacement of ADAM8-Ctrl cells appears to be ADAM8-dependent. As a consequence, the presence of ADAM8 may provide an explanation for the longstanding controversial results of fibronectin enrichment on malignant progression of cancers such as breast cancer. Finally, ADAM8 is apparently essential for providing cell-driven fiber displacements of the extracellular matrix microenvironment, which fosters 3D motility in a fibronectin-rich environment.Contribution to the field. Currently, the role of ADAM8 has been explored in 2D or at maximum 2.5D in vitro cell culture motility assays. However, the mechanical characteristics of these two cell types have not been examined. In this study, the function of ADAM8 in breast cancer is refined by providing in vitro cell investigations in 3D collagen fiber matrices of various conditions. ADAM8 has been shown to be involved in the reduced generation of fiber displacements and in influencing breast cancer cell migration. However, especially in the presence of fibronectin in 3Dcollagen fiber matrices, the fiber displacements of ADAM8-Ctrl cells are increased.

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Section: Discussionmentioning

confidence: 99%

The role of ADAM8 in the mechanophenotype of MDA-MB-231 breast cancer cells in 3D extracellular matrices

Hayn

Fischer

Mierke

2023

Front. Cell Dev. Biol.

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“…A disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin motifs (ADAMTS) are key protease families involved in ECM remodeling; ADAMs modulate cell-ECM interactions and signal transduction through the cleavage of cell surface molecules, while ADAMTS specifically target ECM components such as proteoglycans and collagens, directly contributing to ECM structural changes and functional dynamics. For instance, ADAM8 indirectly contributes to the breakdown and restructuring of the ECM by regulating MMP9 expression, orchestrating the dynamic interplay between these crucial components in ECM remodeling [ 27 , 28 ]. Additionally, other tissue proteases, such as serine, aspartic, and cysteine proteases, also play significant roles in ECM remodeling [ 29 ].…”

Section: The Key Factors For Regulating Ecm Remodelingmentioning

confidence: 99%

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Mai,

Lin,

Lin

et al. 2024

Cell Death Dis

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The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

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“…For instance, according to the mechanisms of tumor cell migration and invasion, ADAM proteinases may direct cell migration through the shedding of cell adhesion molecules or modifying of cell-matrix interaction. Potential substrates involved in cell migration have been summarized in previous reviews [ 58 , 59 ]. Similarly, molecules like ADAM17 have a great number of substrates and are involved in diverse diseases and pathological processes.…”

Section: Link Between Substrate Cleavage and Biological Processes In ...mentioning

confidence: 99%

Role of ADAM and ADAMTS proteases in pathological tissue remodeling

Wang,

Li,

Chen

et al. 2023

Cell Death Discov.

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Pathological tissue remodeling is closely associated with the occurrence and aggravation of various diseases. A Disintegrin And Metalloproteinases (ADAM), as well as A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTS), belong to zinc-dependent metalloproteinase superfamily, are involved in a range of pathological states, including cancer metastasis, inflammatory disorders, respiratory diseases and cardiovascular diseases. Mounting studies suggest that ADAM and ADAMTS proteases contribute to the development of tissue remodeling in various diseases, mainly through the regulation of cell proliferation, apoptosis, migration and extracellular matrix remodeling. This review focuses on the roles of ADAM and ADAMTS proteinases in diseases with pathological tissue remodeling, with particular emphasis on the molecular mechanisms through which ADAM and ADAMTS proteins mediate tissue remodeling. Some of these reported proteinases have defined protective or contributing roles in indicated diseases, while their underlying regulation is obscure. Future studies are warranted to better understand the catalytic and non-catalytic functions of ADAM and ADAMTS proteins, as well as to evaluate the efficacy of targeting these proteases in pathological tissue remodeling.

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The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling

Cited by 8 publications

References 160 publications

The role of ADAM8 in the mechanophenotype of MDA-MB-231 breast cancer cells in 3D extracellular matrices

The role of ADAM8 in the mechanophenotype of MDA-MB-231 breast cancer cells in 3D extracellular matrices

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Role of ADAM and ADAMTS proteases in pathological tissue remodeling

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