Neurotrophins promotes brain metastasis of triple negative breast cancer through Src kinase family activation
2 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
3 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
4 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
5 LilNCog - Lille Neurosciences & Cognition - U 1172
6 PLBS - Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41
7 IEMN - Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520
8 BIOMEMS - IEMN - Bio-Micro-Electro-Mechanical Systems - IEMN
9 JUNIA - JUNIA
10 LIMMS - Laboratory for Integrated Micro Mechatronics Systems
11 HCS-PL - HCS-Pharma Loos [Lille]
12 IJM (UMR_7592) - Institut Jacques Monod
13 INSERM - Institut National de la Santé et de la Recherche Médicale
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Résumé
With nearly 2.3 million cases diagnosed worldwide each year and an estimated 685 000 deaths by 2020, breast cancer is the leading cause of cancer-related death in women. Brain metastases cause severe cognitive complications that severely impair quality of life. In TN breast cancer, the prognosis for brain metastases is particularly poor with a median survival of no more than 6 months. It is therefore crucial to know the molecular actors that promote the metastatic dissemination of triple negative breast cancer to the brain but also to prevent the proliferation of brain micrometastases that can cause fatal recurrences. In order to recapitulate several final stages of brain metastasis, we used both human Blood- Brain-Barrier in vitro model, human organotypic 3D extracellular in vitro matrix, mice brain slices organotypic ex vivo culture and in vivo mice xenograft. These models are coupled with single cell, 3D and real time imaging techniques, including FRET biosensing. This unique experimental approach allows us to study the involvement of signaling pathways in these different biological processes. Using this innovative method, we have identified that inhibition neurotrophins receptor leads to a decrease in the activity of the underlying signaling pathways and consequently to a decrease in the ability of breast cancer cells to pass through the BBB, to grow and to colonize the brain parenchyma.