Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis
Andrew E. Whiteley, Danhui Ma, Lihua Wang, Seok‐Yeong Yu, Claire Yin, Trevor Price, Brennan Simon, Katie R. Xu, Kathleen A. Marsh, Maegan L. Brockman, Tatiana Prioleau, Katherine I. Zhou, Xiuyu Cui, Peter E. Fecci, William R. Jeck, Chad M. McCall, Jadee Neff, Dorothy A. Sipkins
Abstract
The molecular mechanisms that regulate breast cancer cell (BCC) metastasis and proliferation within the leptomeninges (LM) are poorly understood, which limits the development of effective therapies. In this work, we show that BCCs in mice can invade the LM by abluminal migration along blood vessels that connect vertebral or calvarial bone marrow and meninges, bypassing the blood-brain barrier. This process is dependent on BCC engagement with vascular basement membrane laminin through expression of the neuronal pathfinding molecule integrin α6. Once in the LM, BCCs colocalize with perivascular meningeal macrophages and induce their expression of the prosurvival neurotrophin glial-derived neurotrophic factor (GDNF). Intrathecal GDNF blockade, macrophage-specific GDNF ablation, or deletion of the GDNF receptor neural cell adhesion molecule (NCAM) from BCCs inhibits breast cancer growth within the LM. These data suggest integrin α6 and the GDNF signaling axis as new therapeutic targets against breast cancer LM metastasis.