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FIGURE 1 from Integrin-αvβ3 is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance

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posted on 2023-12-07, 14:20 authored by William Echavidre, Jérôme Durivault, Célia Gotorbe, Thays Blanchard, Marina Pagnuzzi, Valérie Vial, Florian Raes, Alexis Broisat, Rémy Villeneuve, Régis Amblard, Nicolas Garnier, Cécile Ortholan, Marc Faraggi, Benjamin Serrano, Vincent Picco, Christopher Montemagno

Integrin-αvβ3 is differentially expressed in medulloblastoma cell lines and promotes their proliferation, migration, and invasion. A, IHC staining of integrin-αvβ3 in human medulloblastomas using tissue array slides (US Biomax, n = 20). Staining intensity was classified as no, low, or moderate expression. B, A heat map showing integrin gene expression in medulloblastoma cell lines quantified by qRT-PCR. Results are expressed in comparison to normal cerebellum (log₁₀-fold change). The mean values of three independent experiments are shown. C, A Western blot analysis of β3-integrin protein expression in medulloblastoma cell lines. D and E, Representative Western blots of β3-integrin expression in DAOY (control vs. KO and β3-integrin–overexpressing cells) and HD-MB03 (LacZ vs. β3-integrin–overexpressing cells) cell lines. Three independent experiments were performed. The proliferation of DAOY_Control, KO_#22, KO_#22-rescue (F, left), KO_#36, KO_#36-rescue (F, right), and HD-MB03-LacZ and overexpressing-β3-integrin (G). Proliferation rates represent the percentage change versus day 0. Three independent experiments were performed, and data are presented as mean ± SEM. The migration of DAOY_Control, KO_#22, KO_#22-rescue (H, left), KO_#36, KO_#36-rescue (H, right), and HD-MB03-LacZ and overexpressing-β3-integrin (I). Serum-starved cells were allowed to migrate for 12 (DAOY) or 24 hours (HD-MB03). Migrations were performed using Boyden chamber assays, and the results are presented as the percentage of control cells. Three independent experiments were performed, and data are expressed as mean ± SEM. The invasion of DAOY_Control, KO_#22, KO_#22-rescue (J, left), KO_#36, KO_#36-rescue (J, right), and HD-MB03-LacZ and overexpressing-β3-integrin (K). Serum-starved cells were allowed to invade for 12 (DAOY) or 24 hours (HD-MB03). Invasions were performed in a Boyden chamber coated with Matrigel, and results are presented as the percentage of control cells. Three independent experiments were performed, and data are presented as mean ± SEM. Key: *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus control; ^##, P < 0.01 versus KO_cells.

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Governement of the principality of Monaco

Fondation Flavien

GEMLUC

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ARTICLE ABSTRACT

Medulloblastoma is one of the most prevalent solid tumors found in children, occurring in the brain's posterior fossa. The standard treatment protocol involves maximal resection surgery followed by craniospinal irradiation and chemotherapy. Despite a long-term survival rate of 70%, wide disparities among patients have been observed. The identification of pertinent targets for both initial and recurrent medulloblastoma cases is imperative. Both primary and recurrent medulloblastoma are marked by their aggressive infiltration into surrounding brain tissue, robust angiogenesis, and resistance to radiotherapy. While the significant role of integrin-αvβ3 in driving these characteristics has been extensively documented in glioblastoma, its impact in the context of medulloblastoma remains largely unexplored. Integrin-αvβ3 was found to be expressed in a subset of patients with medulloblastoma. We investigated the role of integrin-αvβ3 using medulloblastoma-derived cell lines with β3-subunit depletion or overexpression both in vitro and in vivo settings. By generating radioresistant medulloblastoma cell lines, we uncovered an increased integrin-αvβ3 expression, which correlated with increased susceptibility to pharmacologic integrin-αvβ3 inhibition with cilengitide, a competitive ligand mimetic. Finally, we conducted single-photon emission computed tomography (SPECT)/MRI studies on orthotopic models using a radiolabeled integrin-αvβ3 ligand (99mTc-RAFT-RGD). This innovative approach presents the potential for a novel predictive imaging technique in the realm of medulloblastoma. Altogether, our findings lay the foundation for employing SPECT/MRI to identify a specific subset of patients with medulloblastoma eligible for integrin-αvβ3–directed therapies. This breakthrough offers a pathway toward more targeted and effective interventions in the treatment of medulloblastoma. This study demonstrates integrin-αvβ3’s fundamental role in medulloblastoma tumorigenicity and radioresistance and the effect of its expression on cilengitide functional activity.

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Keywords

Preclinical Models Xenograft models Imaging Positron emission tomography (PET)Progression, Invasion & Metastasis Cell adhesion and extracellular matrix Pediatric Cancers Radiobiology Radiation-activated signaling pathways CNS Cancers Drug Targets Radiation Oncology Radioprotectors and radiosensitizers

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