The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Whiteley, A.E., Ma, D. et al. Science. 384, 6702 (2024).
doi: 10.1126/science.adh5548.
Summary of the findings
Summary of the findingsBreast cancer cell (BCC) metastasis to the leptomeninges (LM), the cerebrospinal fluid (CSF)-containing membranes surrounding the brain and spinal cord, is a rapidly fatal disease complication. Despite recent advances in treating brain parenchymal metastasis, standard of care for LM disease (LMD) has remained essentially unchanged for decades. The paucity of targeted molecular therapies to treat LMD is attributed to our poor understanding of the molecular mechanisms governing LM metastasis and the narrow toxicity window of the nervous system.
In this article, the authors show that bone-metastatic BCCs can bypass the blood-brain and blood-CSF barriers and invade the LM along the abluminal surface of emissary vessels connecting the bone marrow to the central nervous system. This process, dependent on BCC α6 integrin-laminin interactions with the vascular basement membrane, is a novel and efficient route of solid tumor LM metastasis. Once in the LM, BCCs are exposed to a tissue niche that is at once a harsh environment for tumor growth due to relative nutrient deprivation and a “sanctuary site” of therapeutic resistance. Little is understood about the role the immune system plays in disease control or tumor promotion in the LM. The authors’ new data shed light on these interactions. Using intravital microscopy, they show that BCCs in the LM are encased by perivascular macrophages that secrete the protective neurotrophin, GDNF, activating NCAM-dependent cell survival pathways in BCCs. This process mimics GDNF/macrophage developmental and neuroprotective pathways and highlights the cunning mechanisms tumors cells can invoke to metastasize successfully.
