Journal Article

Leukaemia hijacks a neural mechanism to invade the central nervous system

Jablonski, Elizabeth M., Warner, Matthew J., Yao, Hisayuki, Cantelli, Gaia, Ridge, Sarah M., Chenn, Anjen, Sipkins, Dorothy A., McCall, Chad M., Ngo, Brandon, Therrien, Joseph, Price, Trevor T., Olivere, Lindsey, Tannheimer, Stacey

2018

Overview

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood–brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin–laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS. Expression of α6 integrin enables acute lymphoblastic leukaemia cells to use neural migratory pathways to invade the central nervous system and metastasize to the brain.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 13/51 / 14/19 / 14/34 / 14/35 / 14/63 / 45/61 / 631/67/1990/283/2125 / 64/60 / 692/699/67/327 / 82 / 82/29 / 82/80 / Acute lymphoblastic leukemia / Analysis / Animals / Antibodies / Antibodies, Neutralizing - immunology / Basement Membrane - metabolism / Blood / Blood circulation / Blood vessels / Blood-brain barrier / Blood-Brain Barrier - metabolism / Bone Marrow / Brain cancer / Brain tumors / Cancer metastasis / Cell growth / Cell migration / Cell Movement / Cells (biology) / Central nervous system / Central Nervous System - blood supply / Central Nervous System - metabolism / Central Nervous System - pathology / Cerebrospinal fluid / Cerebrospinal Fluid - metabolism / Cerebrovascular Circulation / Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Disease Progression / Euthanasia / Experiments / Explosions / Female / Flow cytometry / Heterografts - immunology / Heterografts - pathology / Histology / Humanities and Social Sciences / Integrin alpha6 - immunology / Integrin alpha6 - metabolism / Integrins / Laminin / Laminin - metabolism / Leukemia / Male / Medical research / Metastases / Metastasis / Mice / Mice, SCID / Microscopy / Motility / multidisciplinary / Neoplasm Transplantation / Nervous system / Neural stem cells / Neurons / Parenchyma / Patients / Physiological aspects / Precursor Cell Lymphoblastic Leukemia-Lymphoma - enzymology / Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology / Progenitor cells / Receptors, Laminin - antagonists & inhibitors / Receptors, Laminin - immunology / Receptors, Laminin - metabolism / Rodents / Science / Science (multidisciplinary) / Skull / Solid tumors / Subarachnoid Space / Tumors / Vertebrae / Xenografts / Xenotransplantation