Similar Datasets
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: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.
2020-07-16 | GSE150660 | GEO
Project description:This study aimed to identify specific CSF miRNAs for diagnosing and monitoring leptomeningeal metastasis with lung adenocarcinoma. In discovery phase, we performed miRNA microarray analysis in CSF samples from leptomeningeal metastasis patients and non-leptomeningeal metastasis controls.
2020-02-26 | GSE125191 | GEO
Project description:This study aimed to identify specific CSF miRNAs for diagnosing and monitoring leptomeningeal metastasis with lung adenocarcinoma. In discovery phase, we performed miRNA microarray analysis in matched CSF samples from leptomeningeal metastasis patients at diagnosis and after initial leptomeningeal metastasis-directed therapy.
2020-02-26 | GSE125192 | GEO
Project description:Melanoma brain metastases (MBM) and leptomeningeal metastases (LMM) are two manifestations of melanoma CNS metastasis with vastly different survival outcomes. Using single cell RNA-Seq analysis we uncovered a unique, immune-suppressed T-cell landscape in the LMM microenvironment distinct from that of brain and skin metastases. An LMM patient with an unusually long survival demonstrated an immune repertoire that was distinct from those of poor survivors and more similar to CSF from non-LMM patients. Upon response to PD-1 therapy, this extreme responder showed increased levels of T-cells and dendritic cells in their CSF, whereas poor survivors showed little improvement in their T-cell responses. In MBM patients, systemic therapy was associated with increased immune infiltrate, with similar T-cell transcriptional diversity noted between skin metastases and MBM - suggestive of immune cell trafficking into the brain. A correlation analysis across the entire immune landscape identified the presence of a rare population of dendritic cells (DC3s) that correlated with increased overall survival and positively regulated the immune environment through modulation of activated T-cells and MHC expression. Our study provides the first atlas of two distinct sites of melanoma CNS metastases and identifies rare populations of cells that underlie the biology of this devastating disease.
2021-05-14 | GSE174401 | 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.
2020-07-16 | GSE144848 | GEO
Project description:Single-cell atlas of human leptomeningeal metastasis
| PRJNA633130 | ENA
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 development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the CSF from LMM patients to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells. A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >35 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells, that were subjected to RNA-Seq analysis. Functional assays were performed to validate the pathways identified.Mass spectrometry analyses showed the CSF of most LMM patients to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anti-correlated in the extraordinary responder. RNA-Seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGF-β and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGF-β expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays. These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from LMM patients has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.
2019-11-27 | GSE141021 | GEO
Project description:The development of leptomeningeal melanoma metastases (LMM) is a rare and devastating complication of the late-stage disease, for which no effective treatments exist. Here, we performed a multi-omics analysis of the CSF from LMM patients to determine how the leptomeningeal microenvironment shapes the biology and therapeutic responses of melanoma cells. A total of 45 serial CSF samples were collected from 16 patients, 8 of these with confirmed LMM. Of those with LMM, 7 had poor survival (<4 months) and one was an extraordinary responder (still alive with survival >32 months). CSF samples were analyzed by mass spectrometry and incubated with melanoma cells, that were subjected to RNA-Seq analysis. Functional assays were performed to validate the pathways identified. Mass spectrometry analyses showed the CSF of most LMM patients to be enriched for pathways involved in innate immunity, protease-mediated damage, and IGF-related signaling. All of these were anti-correlated in the extraordinary responder. RNA-Seq analysis showed CSF to induce PI3K/AKT, integrin, B-cell activation, S-phase entry, TNFR2, TGF- and oxidative stress responses in the melanoma cells. ELISA assays confirmed that TGF- expression increased in the CSF of patients progressing with LMM. CSF from poorly responding patients conferred tolerance to BRAF inhibitor therapy in apoptosis assays. These analyses identified proteomic/transcriptional signatures in the CSF of patients who succumbed to LMM. We further showed that the CSF from LMM patients has the potential to modulate BRAF inhibitor responses and may contribute to drug resistance.
2020-01-16 | PXD016002 | Pride