LRP-1 Matricellular Receptor Involvement in Triple Negative Breast Cancer Tumor Angiogenesis
Océane Campion, Jessica Thevenard Devy, Jessica Thevenard Devy, Clotilde Billottet, Christophe Schneider, Nicolas Etique, Jean‐William Dupuy, Anne‐Aurélie Raymond, Camille Boulagnon‐Rombi, Marie Meunier, El‐Hadi Djermoune, Elodie Lelièvre, Amandine Wahart, Camille Bour, Cathy Hachet, Stefano Cairo, Andréas Bikfalvi, Stéphane Dedieu, Jérôme Devy, Jérôme Devy
Abstract
Background: LRP-1 is a multifunctional scavenger receptor belonging to the LDLR family. Due to its capacity to control pericellular levels of various growth factors and proteases, LRP-1 plays a crucial role in membrane proteome dynamics, which appears decisive for tumor progression. Methods: LRP-1 involvement in a TNBC model was assessed using an RNA interference strategy in MDA-MB-231 cells. In vivo, tumorigenic and angiogenic effects of LRP-1-repressed cells were evaluated using an orthotopic xenograft model and two angiogenic assays (Matrigel® plugs, CAM). DCE-MRI, FMT, and IHC were used to complete a tumor longitudinal follow-up and obtain morphological and functional vascular information. In vitro, HUVECs’ angiogenic potential was evaluated using a tumor secretome, subjected to a proteomic analysis to highlight LRP-1-dependant signaling pathways. Results: LRP-1 repression in MDA-MB-231 tumors led to a 60% growth delay because of, inter alia, morphological and functional vascular differences, confirmed by angiogenic models. In vitro, the LRP-1-repressed cells secretome restrained HUVECs’ angiogenic capabilities. A proteomics analysis revealed that LRP-1 supports tumor growth and angiogenesis by regulating TGF-β signaling and plasminogen/plasmin system. Conclusions: LRP-1, by its wide spectrum of interactions, emerges as an important matricellular player in the control of cancer-signaling events such as angiogenesis, by supporting tumor vascular morphology and functionality.