Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and predict extremely poor survival. There are currently no molecularly targeted approaches to prevent LM disease involvement. LM metastases are frequent in hematologic malignancies such as acute lymphoblastic leukemia (ALL), and the incidence in solid tumors is rising. We recently reported a novel mechanism whereby ALL cells invade the central nervous system (CNS) LM by migrating along the abluminal surface of emissary blood vessels that bridge the vertebral and calvarial bone marrow and subarachnoid spaces. ALL cells hijack a neural stem cell developmental migration pathway involving ?6 integrin receptor and laminin binding interactions in order to crawl along the laminin-rich basement membrane of this unique vasculature. These vessels pass from the bone marrow through apertures in the vertebral or calvarial bone to directly enter the LM. Malignant cells expressing the laminin receptor, ?6, invade along the external surface of this bridging vasculature in an integrin-dependent fashion, bypassing the peripheral circulation and the blood brain barrier to efficiently metastasize to the LM. This finding explains the clinical observation that LM metastases frequently occur in the absence of brain parenchymal disease involvement. In this proposal, we will define the signaling events that are activated in leukemic cells upon ?6 integrin-laminin engagement, determine the role of ?6 integrin-laminin interactions in breast cancer leptomeningeal metastasis, and test the efficacy of downstream PI3K inhibition to target this pathway in mouse models of ALL and breast cancer LM metastasis. These studies will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach to an area of high unmet clinical need.

Public Health Relevance

Cancer metastases to the leptomeninges (LM) are difficult to treat, create significant morbidity, and portend extremely poor survival. Our proposed work will define how malignant cells hijack developmental neuronal pathfinding mechanisms to enter the central nervous system. Our studies will provide new mechanistic insight into a poorly understood biologic phenomenon and a therapeutic approach to an area of high unmet clinical need.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA234580-01A1
Application #
9888134
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Snyderwine, Elizabeth G
Project Start
2020-01-06
Project End
2024-12-31
Budget Start
2020-01-06
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705