Single-cell atlas of dura cells from non-tumor or leptomeningeal metastasis mice
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ABSTRACT:
PROVIDER: PRJNA1111058 | ENA |
REPOSITORIES: ENA
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Project description:The tumor microenvironment plays a critical regulatory role in cancer progression, especially in metastases to the central nervous system. Cancer cells inhabiting the cerebrospinal spinal fluid (CSF)-filled leptomeningeal space face substantial microenvironmental challenges including inflammation and sparse extracellular iron. Unlike CSF leukocytes, we find that cancer cells within the CSF express the iron-binding protein LCN2 and its receptor SCL22A17. Employing mouse models of LM, we find that the LCN2/SLC22A17 system is necessary to support leptomeningeal cancer cell growth. We find that infiltrating CSF macrophages generate inflammatory cytokines that induce cancer cell LCN2 expression. This LCN2/SLC22A17 system provides cancer cells superior access to limiting extracellular iron, allowing LCN2-expressing cancer cells to outcompete CSF macrophages for this resource. Finally, pharmacologic interruption of these interactions prevents cancer cell growth within the leptomeninges.
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Project description:Little is understood about the gene expression changes that underlie cancer spread to the cerebrospinal fluid, or leptomeningeal metastasis. Using four cancer cell line models, we empolyed iterative in vivo selection to generate subpopulations of these cell lines able to access the leptomeningeal space and grow once there. We compared the gene expression profile of the terminally selected cells or "Lep" cells with that of the parental or "Par" cells, as well as that of an intermediate stage of in vivo selection or "Int" cells. Analyses for brain parenchymal metastatic derivatives or "BrM" cells were included for comparison.
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Project description:Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-gamma signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. We find that transgenic host mice, lacking IFN-gamma or its receptor, fail to control LM growth. Overexpression of Ifng through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-gamma actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-gamma signaling and suggests a novel immune-therapeutic approach against tumors within this space.
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