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FIGURE 3 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

Pharmacologic disruption of integrin-αvβ3 impairs downstream signaling, decreasing cell proliferation, migration, and invasion of DAOY. Representative Western blots depicting FAK, Akt, and ERK1/2 activation in DAOY cells following treatment with cilengitide (1 hour of treatment with 1, 5, or 25 µmol/L cilengitide) in A or LM609 (30, 60, or 90 minutes of treatment with 10 µg/mL LM609) in B. Three independent experiments were conducted. Evaluation of DAOY cell proliferation after treatment with cilengitide (0.5 or 2.5 µmol/L) in C or LM609 (1 and 10 µg/mL) in D for 96 hours. Proliferation rates are expressed as a percentage of day 0. Three independent experiments were performed, and data are presented as mean ± SEM. Invasion assays for DAOY cells treated with cilengitide (E) or LM609 (F) for 12 hours. Serum-starved cells were exposed to cilengitide (0.5 or 2.5 µmol/L) in E or LM609 (1 and 10 µg/mL) in F and allowed to invade for 12 hours. Invasion assays were conducted using Matrigel-coated Boyden chamber assays, and the results are expressed as a percentage relative to control cells. Three independent experiments were carried out, and data are presented as mean ± SEM. Key: *, P < 0.05; **, P < 0.01; ***, P < 0.001 versus indicated conditions.

Funding

Governement of the principality of Monaco

Fondation Flavien

GEMLUC

History

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.