Single cell characterization of the immune microenvironment of melanoma brain and leptomeningeal metastases
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PROVIDER: PRJNA729750 | ENA |
REPOSITORIES: ENA
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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 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
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: Not available
| S-EPMC8282775 | biostudies-literature
Project description:Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. This study aims to characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomic analyses.
2024-06-03 | GSE250636 | GEO
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. Seventy-two samples from 52 brain (except for patient 01, who had a spinal cord metastasis) and extracranial metastases of melanoma were analyzed. Available biological replicates (different parts of the same tumor) were included.
2014-05-08 | E-GEOD-50493 | biostudies-arrayexpress
Project description:Cerebrospinal fluid cells derived from one breast cancer leptomeningeal metastases patient
2022-05-12 | GSE202501 | GEO
Project description:An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and protein expression and activation, quantitatively analyzed by molecular inversion probe arrays, microarrays and reverse phase protein array (RPPA) were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors.
2014-05-08 | GSE50493 | GEO
Project description:This is a whole exome study of brain metastases in melanoma. We are studying the genomic evolution of primary cutaneous melanoma to brain met in patients with brain-only metastatic disease. We are also looking at the genomic heterogeneity in patients with temporally, anatomically and regionally separated brian metastases.
| EGAS00001002107 | EGA
Project description:Metastasis is the deadliest phase of cancer progression. Experimental models using immunodeficient mice have been used to gain insights into the mechanisms of metastasis. We report here the identification of a “metastasis aggressiveness gene expression signature” derived using human melanoma cells selected based on their metastatic potentials in a xenotransplant metastasis model. Comparison with expression data from human melanoma patients shows that this metastasis gene signature correlates with the aggressiveness of melanoma metastases in human patients. Many genes encoding secreted and membrane proteins are included in the signature, suggesting the importance of tumor-microenvironment interactions during metastasis. Keywords: disease state
2007-10-02 | GSE8401 | GEO