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    Team: Leukemia and niche dynamics

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    Team leader

    Our lab is interested in exploring the mechanisms regulating cell-cell interaction in the bone marrow tissue during leukemogenesis. The vascularized BM tissue is a multicellular unit highly interconnected with the haematopoietic system in health and disease. How these different components participate into the development of acute leukemia is a fundamental missing piece of the puzzle. By combining cutting edge strategies such as intravital two-photon microscopy and tissue bioengineering, we aim at deciphering the role of specific mediators of these processes in the context of acute leukemia.

     

    Objectives

    The lab has three major research lines:

    • Endothelial adhesion in acute leukemia:

    Vascular function is tightly regulated by structural and architectural cues. Several functional abnormalities in the bone marrow (BM) vasculature have been reported (e.g. increased permeability, altered perfusion and loss of healthy hematopoietic stem cells). High throughput RNA-sequencing analysis of BM-derived endothelial cells (ECs) have shown multiple molecular alterations (Passaro et al., Cancer Cell 2017).  By using intravital 2P imaging and transgenic mouse models, we investigate how the pathologic remodeling of adhesion molecules in the endothelium mediates the leukemia interaction with the niche and support leukemia growth.

    • Bioengineering the bone marrow niche

    Vascular remodelling is a complex multi-steps process, resulting from a balance between growth and regression. The bone marrow (BM) vascular system is intrinsically connected with the surrounding tissue matrix, the bone, and these two structures develop together in an intricate network of mutual signals (Passaro et al., Jove 2017; Abarrategi et al., J Exp Med. 2018). We will explore the novel frontiers of 3D bio-printing to bioengineer in vitro a complex tissue mimicking the vascularized BM, providing an alternative flexible tool where genetically or pharmacologically manipulate individual cell types in a highly controllable manner and analyse the response of the vasculature to specific leukemia-driven stimuli.

    • Bone marrow niche across leukemias: same host, different guests

    The BM niche is constantly challenged by external insults, which affect the way it functions and feedbacks in turn to re-establish the homoeostatic balance. Leukemia, amongst the others, can be a long-lasting insult progressively expanding in the tissue and altering its function (Passaro et al., Immunol Rev. 2016). However, the type of interaction leukemic cells establish with environmental components is quite peculiar and specific to the nature of the cells. We aim to explore the differential alteration of the BM niche during acute myeloid and lymphoid leukemias to improve the knowledge of the differences between these diseases and identify specific novel targets.

     

    Main publications

    Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. Passaro D, Di Tullio A, Abarrategi A, Rouault-Pierre K, Foster K, Ariza-McNaughton L, Montaner B, Chakravarty P, Bhaw L, Diana G, Lassailly F, Gribben J, Bonnet D. Cancer Cell. 2017 Sep 11;32(3):324-341.e6. doi: 10.1016/j.ccell.2017.08.001. Epub 2017 Sep 1. PMID: 28870739

    Bioengineering of Humanized Bone Marrow Microenvironments in Mouse and Their Visualization by Live Imaging. Passaro D, Abarrategi A, Foster K, Ariza-McNaughton L, Bonnet D. J Vis Exp. 2017 Aug 1;(126). doi: 10.3791/55914. PMID: 28809828

    T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Hawkins ED*, Duarte D*, Akinduro O#, Khorshed RA#, Passaro D#, Nowicka M, Straszkowski L, Scott MK, Rothery S, Ruivo N, Foster K, Waibel M, Johnstone RW, Harrison SJ, Westerman DA, Quach H, Gribben J, Robinson MD, Purton LE, Bonnet D, Lo Celso C. Nature. 2016 Oct 27;538(7626):518-522. doi: 10.1038/nature19801. Epub 2016 Oct 17. PMID: 27750279

    Microenvironmental cues for T-cell acute lymphoblastic leukemia development. Passaro D, Quang CT, Ghysdael J. Immunol Rev. 2016 May;271(1):156-72. doi: 10.1111/imr.12402. Review. PMID: 27088913

    CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia. Passaro D, Irigoyen M, Catherinet C, Gachet S, Da Costa De Jesus C, Lasgi C, Tran Quang C, Ghysdael J. Cancer Cell. 2015 Jun 8;27(6):769-79. doi: 10.1016/j.ccell.2015.05.003. PMID: 26058076

     

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