Abstract PO020: The matricellular receptor LRP-1 acts as a pro-tumorigenic receptor by supporting tumor angiogenesis in a triple negative breast cancer model
Authors: Océane Campion, Jessica Thevenard-Devy, Nicolas Etique, Anne-Aurélie Raymond, Jean-William Dupuy, Stéphane Dedieu, Jérôme Devy
Journal: Cancer Research (2021)

Abstract LRP-1 (low-density lipoprotein receptor-related protein-1) receptor is a multifunctional endocytosis receptor that is part of the LDL receptor family. Due to its capacity to control the pericellular level of various growth factors and proteases, LRP-1 plays a crucial role in controlling the dynamics of the membrane proteome. [1] LRP-1 overexpression in breast cancer and in particular in triple negative breast cancer (TNBC), prompted us to take an interest in its involvement in tumor progression and more specifically to the role it could play in controlling angiogenesis. For that purpose, an RNA interference strategy in a TNBC model (MDA-MB-231 line) in vivo was used, based on shRNA stable expression. 42 days following an orthotopic injection of shLRP-1 MDA-MB-231 cells (in which LRP-1 expression is repressed by 70%) and shCtrl MDA-MB-231 cells (comparable to wild type MDA-MB-231 cells) in BALB/c nude mice, a delay of 40% in tumor growth was observed (257 mm3 vs 432 mm3, p &amp;lt;0.05) (n = 15 per group). The concomitant use of complementary preclinical imaging modalities, namely magnetic resonance imaging (DCE-MRI) and fluorescence molecular tomography (FMT), allowed us to complete a longitudinal follow-up of tumor development and, especially, tumor angiogenesis. Morphological and functional information obtained on the tumor and its vascularization, supplemented and confirmed by immunohistochemical analyzes, allowed us to highlight that LRP-1 act as a pro-tumorigenic receptor in TNBC progression in vivo by, among other things, upholding tumor angiogenesis. In vitro, using tumor conditioned media (TCM) from MDA-MB-231 shLRP-1 compared to shCtrl, we showed that the secretome of these cancer cells can differentially modulate three-dimensional tubular network formation as well as migrative and proliferative capacities of human umbilical vein endothelial cells (HUVECs). A proteomic analysis (in collaboration with the CGFB plateform proteome (Bordeaux, France)) of these TCM allowed us to identify numerous angiogenesis molecular targets significantly modulated by LRP-1 repression. This revealed unstable angiogenic balance of growth factors, cytokines and proteases orchestrated by the lack of LRP1 expression strengthen LRP-1 non-negligible role in tumor angiogenesis and constitute a wealth of information to provide a better understanding of its regulatory action within the TNBC microenvironment. [1] Lillis AP, Van Duyn LB, Murphy-Ullrich JE, and Strickland DK. LDL Receptor-Related Protein 1: Unique Tissue- Specific Functions Revealed by Selective Gene Knockout Studies. Physiol Rev. 2008; 88: 887918 Citation Format: Océane Campion, Jessica Thevenard-Devy, Nicolas Etique, Anne-Aurélie Raymond, Jean-William Dupuy, Stéphane Dedieu, Jérôme Devy. The matricellular receptor LRP-1 acts as a pro-tumorigenic receptor by supporting tumor angiogenesis in a triple negative breast cancer model [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO020.