Immunocompetent models of brain parenchymal and leptomeningeal metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221358 | GEO | 2023/03/27
REPOSITORIES: GEO
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Project description:Meninges, or the membranous coverings of the brain and spinal cord, play host to dozens of morbid pathologies. In this study we provide a method to isolate the leptomeningeal cell layer, identify leptomeninges in histologic slides, and maintain leptomeningeal fibroblasts in in vitro culture. Using an array of transcriptomic, histological, and cytometric analyses, we identified ICAM1 and SLC38A2 as two novel markers of leptomeningeal cells in vivo and in vitro. Our results confirm the fibroblastoid nature of leptomeningeal cells and their ability to form a sheet-like layer that covers the brain and spine parenchyma. These findings will enable researchers in central nervous system barriers to describe leptomeningeal cell functions in health and disease.
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Project description:Microglial cells are the resident macrophages of the brain. Perivascular macrophages (PVM) are also myeloid resident cells that are located at the interface between blood, CSF and brain in the perivascular space. Due to their strategic location and their ability to sample CSF content, we hypothesized that PVM might play a role in CSF flow. Using different fluorescent tracers injected either into the CSF (influx) or the brain parenchyma (efflux) we assessed their spatio-temporal distribution and found that ablation (using clodronate liposomes) or dysfunction (using genetic tools) of PVM alters CSF dynamics and patterns. Using single cell RNA sequencing, we found that PBMs can be divided in two sub-populations, and that one population of PBMs could interact with vascular smooth muscle cells, which allow arterial pulsations and subsequently CSF flow. Interestingly, aging results in altered PVM phenotype, and reversing this phenotype using macrophage specific grown factors reversed some of aging-associated dysfunctions of CSF flow. In summary, our results identify a new role of PVM in CSF flow and open new avenues for therapeutical applications targeting PVM in neurodegenerative diseases such as Alzheimer’s disease.
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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.
2023-03-27 | GSE221593 | GEO
Project description:Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC- and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with 9-cis RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro. In vivo, whereas knockout of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby locally-generated developmental cues metabolically reprogram metastatic cancer cells and suggest novel therapeutic approaches.
2024-10-13 | GSE278624 | GEO
Project description:Cancer cells metastatic to the leptomeninges encounter a metabolically-challenging extreme microenvironment. To understand adaptations to this space, we subjected leptomeningeal-metastatic (LeptoM) mouse breast and lung cancers isolated from either the leptomeninges or orthotopic primary sites to ATAC- and RNA-sequencing. When inhabiting the leptomeninges, the LeptoM cells demonstrated transcription downstream of retinoid-X-receptors (RXRs). We found evidence of local retinoic acid (RA) generation in both human leptomeningeal metastasis and mouse models in the form of elevated spinal fluid retinol and expression of RA-generating dehydrogenases within the leptomeningeal microenvironment. Stimulating LeptoM cells with 9-cis RA induced expression of transcripts encoding de novo fatty acid synthesis pathway enzymes in vitro. In vivo, whereas knockout of Stra6 did not alter cancer cell leptomeningeal growth, knockout of Rxra/b/g interrupted cancer cell lipid biosynthesis and arrested cancer growth. These observations illustrate a mechanism whereby locally-generated developmental cues metabolically reprogram metastatic cancer cells and suggest novel therapeutic approaches.
2024-10-13 | GSE277504 | GEO
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:Leptomeningeal metastasis (LM), or spread of cancer cells into the cerebrospinal fluid, is characterized by a rapid onset of debilitating neurological symptoms and markedly bleak prognosis. The lack of reproducible in vitro and in vivo models has prevented development of novel, LM-specific therapies. Although LM allows for longitudinal sampling of floating cancer cells with a spinal tap, attempts to culture patient-derived leptomeningeal cancer cells have not been successful. We therefore employ leptomeningeal derivatives of human breast and lung cancer cell lines that reproduce both floating and adherent phenotypes of human LM in vivo and in vitro. We introduce a trypsin/EDTA-based fractionation method to reliably separate the two cell subsets and demonstrate that in vitro cultured floating cells have decreased proliferation rate, lower ATP content, and are enriched in distinct metabolic signatures. Long-term fractionation and transcriptomic analysis suggest a high degree plasticity between the two phenotypes in vitro. Floating cells colonize mouse leptomeninges more rapidly and associate with shortened survival. In addition, patients harboring LM diagnosed with CSF disease alone succumbed to the disease earlier than patients with adherent (MRI-positive) disease. Together, these data support mechanistic evidence of a metabolic adaptation that allows cancer cells to thrive in their natural environment but leads to death in vitro.
2020-01-21 | GSE137020 | GEO
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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