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Principal Investigator: Dorothy A Sipkins
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $494,502
Funding agency: National Cancer Institute
Leptomeningeal (LM) metastases occur in a wide variety of hematologic and solid malignancies, including
leukemia, breast cancer (BC), and lung cancer. When LM metastases arise, they are almost always rapidly fatal,
causing severe neurologic symptoms and death within weeks to months. The molecular mechanisms that enable
LM metastasis have been poorly understood, and there are currently few targeted interventions to prevent or
treat this deadly disease complication. Our lab recently made the seminal discovery of a direct cell trafficking
pathway between the vertebral and calvarial bone marrow (BM) and the adjacent CNS LM. We initially
demonstrated this pathway in acute lymphoblastic leukemia (ALL) mouse models, showing that ALL cells invade
the central LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and
calvarial BM and subarachnoid spaces. These emissary blood vessels, whose basement membrane is highly
enriched in the extracellular matrix molecule laminin, pass from the BM through apertures in the vertebral or
calvarial bone to enter the LM. ALL cells crawl along the outside of this emissary vasculature by binding laminin
via cell surface integrin α6 laminin receptors, circumventing the blood brain barrier (BBB) to efficiently
metastasize to LM by this perivascular route. Subsequent work has shown that this direct cell trafficking pathway
between BM and LM is also used by immune cells to rapidly respond to CNS inflammation, although whether
this pathway is important for tumor-immune responses is unknown. It is also unknown whether continued tumor
integrin α6 interactions within the LM membranes, which highly express laminin, are important to sustain tumor
growth in the LM microenvironment. Our new data in mouse breast cancer (BC) LMD models show that
solid tumors can enter the LM through this novel BM-to-meninges perivascular migration pathway and
suggest that the high affinity laminin receptor, α6 integrin, is a critical target to prevent breast cancer
LMD. These data also demonstrate a crucial role for perivascular macrophages in promoting BC LMD.
Our proposal aims to further our understanding of the interplay between laminin-rich emissary vessels, meninges,
tumor cells, and immune cells in LM metastasis, in order to expose novel approaches to augment therapeutic
responses in the “sanctuary” of the LM. Through cutting-edge spatial transcriptomic analyses and real-time in
vivo imaging approaches, our work will also create an unprecedented understanding of the tumor
microenvironment of the LM niche, and how this laminin-rich environment contributes to disease survival and
proliferation. Finally, we will seek to translate these discoveries into clinical practice through an understanding of
how integrin α6 blockade can be used to prevent and treat LMD in preclinical models of BC LM metastasis. Our
approach represents a shift in the treatment paradigm for LMD, away from minimally effective cytotoxic therapies
toward molecularly targeted exploitation of microenvironment-based vulnerabilities.
Terms: <Abscission><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Adaptive Immune System><Affect><Affinity><Anatomic Sites><Anatomic structures><Anatomy><Antibodies><Apoptosis><Apoptosis Pathway><Area><BBB crossing><Basement membrane><Binding><Biologic Phenomena><Biological Phenomena><Blood - brain barrier anatomy><Blood Vessels><Blood monocyte><Blood-Brain Barrier><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain Metastasis><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Prevention><Breast Metastasis><Breast Tumor Patient><Breast tumor model><Bypass><CD49f Antigens><CNS Nervous System><Calvaria><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Cycle Progression><Cell Interaction><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cell surface><Cell-Extracellular Matrix><Cell-to-Cell Interaction><Cells><Cellular Migration><Cellular Motility><Central Nervous System><Cessation of life><Clinical><Clinical Treatment Moab><Collaborations><Complication><Confocal Microscopy><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Death><Development><Disease><Disease Progression><Disorder><ECM><Environment><Event><Excision><Exhibits><Exposure to><Extirpation><Extracellular Matrix><GDNF><GDNF gene><Glycoprotein GP-2><Hemato-Encephalic Barrier><Hematology><Heterograft><Heterologous Transplantation><Hortega cell><Host-Tumor Interaction><Human><Hypoxia><Hypoxic><Immune><Immune Globulins><Immune response><Immunes><Immunoglobulins><Immunological response><Inflammation><Innate Immune System><Integrin alpha6><Integrin α6><Integrins><Integrins Extracellular Matrix><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intraventricular><Invaded><Laminin><Laminin Receptor><Leptomeningeal Metastasis><Leptomeningeal Neoplasms><Leptomeningeal Tumor><Leptomeninges><Leptomeninges Tumor><MAb Therapeutics><Macrophage><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Marrow monocyte><Mediating><Membrane><Meningeal><Meningeal Carcinomatosis><Meninges><Metabolic Processes><Metabolism><Metastasis><Metastasis to the Leptomeninges><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Brain><Metastatic Neoplasm to the Leptomeninges><Metastatic Tumor><Metastatic Tumor to the Brain><Metastatic Tumor to the Leptomeninges><Metastatic breast cancer><Metastatic malignant neoplasm to brain><Mice><Mice Mammals><Microglia><Modern Man><Molecular><Molecular Interaction><Molecular Target><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><Neoplasm Metastasis><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neuraxis><Neurocyte><Neurologic Body System><Neurologic Manifestations><Neurologic Organ System><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Neurons><Nutrient><Operative Procedures><Operative Surgical Procedures><Oxygen Deficiency><Pathogenesis><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Play><Pre-Clinical Model><Preclinical Models><Preclinical Testing><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Process><Programmed Cell Death><Proliferating><Pulmonary Cancer><Pulmonary malignant Neoplasm><Removal><Reporting><Robin><Robin bird><Role><Route><Sampling><Secondary Neoplasm><Secondary Tumor><Seminal><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skull><Solid><Solid Neoplasm><Solid Tumor><Stress><Subarachnoid Space><Surface><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Testing><Therapeutic><Therapeutic Monoclonal Antibodies><Time><Toxic effect><Toxicities><Transgenic Mice><Translating><Tumor Cell><Tumor Cell Invasion><Tumor Invasion><Vertebrae><Vertebral><Vertebral Bone><Work><Xenograft><Xenograft procedure><Xenotransplantation><acquired immune system><acute lymphatic leukemia><acute lymphoblastic leukemia cell><acute lymphocytic leukemia cell><acute lymphogenous leukemia><acute lymphoid leukemia cell><acute lymphomatic leukemia><alpha(6) Integrin><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biological signal transduction><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><bone><brain micrometastasis><breast cancer metastasis><breast cancer survival><breast tumor cell><calvarial><cancer cell><cancer metastasis><cancer microenvironment><cell motility><clinical practice><compact bone><cortical bone><cranium><cytotoxic><developmental><disease model><disorder model><effective therapy><effective treatment><experience><gitter cell><glial cell-line derived neurotrophic factor><host neoplasm interaction><host response><imaging approach><imaging based approach><imaging in vivo><immune system response><immunoresponse><in vivo imaging><insight><interventional strategy><leptomeninges neoplasm><leukemia><lung cancer><mAbs><malignancy><malignant breast tumor><mammary cancer model><mammary cancer prevention><mammary tumor model><mammary tumor prevention><membrane structure><meninge><meningeal metastases><mesoglia><metastatic process><microglial cell><microgliocyte><migration><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><monoclonal Abs><monoclonal antibody drugs><monocyte><mouse model><murine model><neoplasm/cancer><neoplastic cell><neoplastic meningitis><neural manifestation><neuronal><neurotrophic factor><neurotrophin><neutralizing antibody><neutrophin><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><patient oriented outcomes><perivascular glial cell><pre-clinical testing><prevent><prevent breast cancer><preventing><recruit><resection><response><response to therapy><response to treatment><scaffold><scaffolding><social role><spine bone structure><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic evaluation><therapeutic mAbs><therapeutic response><therapeutic testing><therapy response><trafficking><transcriptomics><treatment response><treatment responsiveness><tumor><tumor behavior><tumor cell metastasis><tumor growth><tumor microenvironment><tumorigenic><vascular><xeno-transplant><xeno-transplantation>