Combined Radiochemotherapy: Metalloproteinases Revisited

Waller, Verena; Pruschy, Martin

doi:10.3389/fonc.2021.676583

Cited by 11 publications

(6 citation statements)

References 185 publications

(244 reference statements)

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“…Another adipogenic marker, TIMP1 (tissue inhibitor of matrix metalloproteinase 1), was also increased in the circulation of DIO mice. TIMP1 has been reported to promote cell proliferation in TNBC and can modulate the radiosensitivity of cancer cells based on its enzymatic inhibition characteristics [59][60][61]. Whether TIMP1 plays a role in coordination with SERPINE1 in this scenario warrants further investigation.…”

Section: Discussionmentioning

confidence: 98%

Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer

Ann

et al. 2023

Cell Death Dis

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Obesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients’ BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.

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Section: Discussionmentioning

confidence: 98%

Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer

Ann

et al. 2023

Cell Death Dis

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“…We recently reported that IR-induced endothelial cell migration is strongly mediated by tumor cell-located ADAM17 ( 19 , 21 ). In subcutaneous and orthotopic lung tumor models, ADAM17 inhibition by the novel ADAM17-specific therapeutic antibody MEDI3622 in combination with radiotherapy induced a strong anti-angiogenic effect and tumor shrinkage ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…We here describe a unique interrelation between EphA2 and the disintegrin and metalloproteinase ADAM17 alone and in response to irradiation. ADAM17 is involved in the processing of the extracellular matrix and the release of various growth factors and cytokines that contribute to the remodeling of the TME and facilitate tumor cell dissemination ( 19 ). We recently have shown that IR enhances ADAM17 activity in NSCLC cell lines which contributes not only to the radioprotection of the tumor itself, but also its vasculature ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

The role of EphA2 in ADAM17- and ionizing radiation-enhanced lung cancer cell migration

Waller

Tschanz²,

Winkler³

et al. 2023

Front. Oncol.

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PurposeIonizing radiation (IR) enhances the migratory capacity of cancer cells. Here we investigate in non-small-cell-lung-cancer (NSCLC) cells a novel link between IR-enhanced ADAM17 activity and the non-canonical pathway of EphA2 in the cellular stress response to irradiation.MethodsCancer cell migration in dependence of IR, EphA2, and paracrine signaling mediated by ADAM17 was determined using transwell migration assays. Changes of EphA2 pS897 and mRNA expression levels upon different ADAM17-directed treatment strategies, including the small molecular inhibitor TMI-005, the monoclonal antibody MEDI3622, and shRNAs, were mechanistically investigated. ADAM17-mediated release and cleavage of the EphA2 ligand ephrin-A1 was measured using ELISA and an acellular cleavage assay.ResultsIrradiation with 5 Gy enhanced tumor cell migration of NSCLC NCI-H358 cells in dependence of EphA2. At the same time, IR increased growth factor-induced EphA2 S897 phosphorylation via auto- and paracrine signaling. Genetic and pharmaceutical downregulation of ADAM17 activity abrogated growth factor (e.g. amphiregulin) release, which reduced MAPK pathway-mediated EphA2 S897 phosphorylation in an auto- and paracrine way (non-canonical EphA2-pathway) in NCI-H358 and A549 cells. These signaling processes were associated with reduced cell migration towards conditioned media derived from ADAM17-deficient cells. Interestingly, ADAM17 inhibition with the small molecular inhibitor TMI-005 led to the internalization and proteasomal degradation of EphA2, which was rescued by amphiregulin or MG-132 treatment. In addition, ADAM17 inhibition also abrogated ephrin-A1 cleavage and thereby interfered with the canonical EphA2-pathway.ConclusionWe identified ADAM17 and the receptor tyrosine kinase EphA2 as two important drivers for (IR-) induced NSCLC cell migration and described a unique interrelation between ADAM17 and EphA2. We demonstrated that ADAM17 influences both, EphA2 (pS897) and its GPI-anchored ligand ephrin-A1. Using different cellular and molecular readouts, we generated a comprehensive picture of how ADAM17 and IR influence the EphA2 canonical and non-canonical pathway in NSCLC cells.

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“…However, these inhibitors also demonstrated an increased affinity toward the related matrix metalloproteinase ADAM10. Only in the last decade, highly specific anti-human ADAM17-directed antibodies were developed binding ADAM17 in subnanomolar ranges ( 23 ). Characteristic for MEDI3622 is its high target sensitivity as it recognizes the surface loop sIVa- sIVb β-hairpin on the M-domain, unique for ADAM17 ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy

Tschanz

Bender

Telarovic

et al. 2021

Cancer Research Communications

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The cellular response to ionizing radiation (IR) depends on tumor cell and microenvironmental factors. Here, we investigated the role of IR-induced ADAM17 matrix metalloproteinase activity for the intercellular communication between tumor cells and the tumor vasculature in non–small cell lung cancer (NSCLC) tumor models. Factors shed by ADAM17 from NSCLC tumor cells (A549, H358) and relevant for endothelial cell migration were investigated using transwell migration assays, ELISA, and flow cytometry. Tumor angiogenesis–related endpoints were analyzed with the chorio-allantoic membrane assay and in murine NSCLC tumor models. Efficacy-oriented experiments were performed in a murine orthotopic NSCLC tumor model using irradiation with an image-guided small-animal radiotherapy platform alone and in combination with the novel ADAM17-directed antibody MEDI3622. In vitro, VEGF was identified as the major factor responsible for IR-induced and ADAM17-dependent endothelial cell migration toward attracting tumor cells. IR strongly enhanced tumor cell–associated ADAM17 activity, released VEGF in an ADAM17-dependent manner, and thereby coordinated the communication between tumor and endothelial cells. In vivo, tumor growth and microvessel size and density were strongly decreased in response to the combined treatment modality of IR and MEDI3622 but not by either treatment modality alone and thus suggest that the supra-additive effect of the combined treatment modality is in part due to abrogation of the ADAM17-mediated IR-induced protective effect on the tumor vasculature. Furthermore, we demonstrate that the novel ADAM17-inhibitory antibody MEDI3622 potently improves the radiotherapy response of NSCLC. Significance: The tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC.

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Combined Radiochemotherapy: Metalloproteinases Revisited

Cited by 11 publications

References 185 publications

Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer

Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer

The role of EphA2 in ADAM17- and ionizing radiation-enhanced lung cancer cell migration

The ADAM17-directed Inhibitory Antibody MEDI3622 Antagonizes Radiotherapy-induced VEGF Release and Sensitizes Non–Small Cell Lung Cancer for Radiotherapy

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