Therapeutic targeting of the pre-metastatic stage in human brain metastasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE110495 | GEO | 2019/09/24
REPOSITORIES: GEO
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Project description:Therapeutic targeting of the pre-metastatic stage in human brain metastasis
| PRJNA433863 | ENA
Project description:Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We utilized pairs of brain metastasis-derived (BM) and non-brain metastasis-derived (NBM) melanoma short term cultures (STCs) obtained from the same patient. We performed TMT based multiplexed analysis of these cell lines using off-line fractionation to increase our proteomics coverage. Our unbiased proteomics analysis of these melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta for growth and survival in the brain parenchyma. Melanoma-secreted A beta activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Abeta decreases brain metastatic burden.
2022-02-10 | MSV000088814 | MassIVE
Project description:Comparison between the copy number of differentially methylated sites between lymph node metastasis from melanoma patients with good prognosis and melanoma brain metastasis. All samples are taken from different patients, and were established as cell lines in the John Wayne Cancer Institute. Sixteen metastatic melanomas were run on Affymetrix Genome-Wide Human SNP Array 6.0. Lymph node metastases and brain metastases genetic copy number variations were compared.
2013-09-19 | E-GEOD-44019 | biostudies-arrayexpress
Project description:Exclusion of cancer patients with brain metastases from clinical trials is a major cause of the limited therapeutic options available for secondary brain tumors. Here, we report a novel drug-screening platform (METPlatform) based on organotypic cultures that allows identifying anti-metastatic compounds in a preparation that includes the tumor microenvironment. By applying this approach to brain metastasis, we identified HSP90 as a promising therapeutic target. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
2022-03-17 | PXD020092 | Pride
Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. We aimed to find brain metastasis-specific molecular markers. To identify alterations in DNA methylation related to brain metastasis, we used Illumina 450K BeadChips to assess differentially methylated regions in melanocytes, primary melanomas, lymph node metastases, and brain metastases. Bisulphite-converted DNA from 40 specimens was hybridised to the Illumina Infinium 450k Human Methylation BeadChip.
2013-09-19 | E-GEOD-44661 | biostudies-arrayexpress
Project description:We use single cell RNA-seqencing (Drop-seq based) to profile and compare (1) the transcriptomes of naïve brain myeloid cells from wild type C57Bl/6 mice to brain metastasis-associated myeloid cells (Br.MAM) from C57Bl/6 mice bearing E0771 brain metastases and (2) the transcriptomes of Br.MAM in Cx3cr1+/- (het) mouse hosts bearing E0771 brain metastases to Br.MAM in Cx3cr1-/- (KO) mouse hosts bearing E0771 brain metastases.
2021-08-21 | GSE119229 | GEO
Project description:Immunotherapies against brain metastases have shown clinical benefits mainly when applied to locally asymptomatic patients. It is currently unclear why responses to this therapy drop in symptomatic brain metastases, since the use of corticoids is not consistently involved. We report here that a subpopulation within STAT3+ brain metastasis-associated astrocytes is responsible to block the anti-tumor activity of infiltrating CD8+ T cells. The underlying molecular crosstalk involving astrocyte-secreted TIMP1 signaling on CD63+ CD8+ T cells proves a strong immunomodulatory role of astrocytes in the context of brain metastases. By using genetic and pharmacologic approaches applied not only to mouse models, but also to alive human brain metastases we conclude that a combined immunotherapy blocking this local immunosuppressive hub could benefit patients with symptomatic brain metastases. Furthermore, the detection of TIMP1 in the CSF provides a biomarker to select patients for this therapeutic approach. Our findings uncover the importance of dissecting the heterogeneity within the microenvironment at the functional level and the emerging cellular networks to improve the efficacy of organ-specific therapies in metastasis.
2024-08-27 | PXD040436 | Pride
Project description:Melanoma is one of the most aggressive and treatment-resistant cancers. It represents the most life-threatening neoplasm of the skin, and its incidence has been increasing for the last three decades. Melanoma evolves from the local transformation of melanocytes to primary tumors, which can metastasize to multiple organs. Brain metastases represent one of the most significant causes of death in cutaneous melanoma patients. Despite aggressive multi-modality threapy, patients with melanoma brain metastasis have a median survival of less than a year, with a majority of these patients dying as a result of their intracranial disease. We aimed to find brain metastasis-specific molecular markers. To identify alterations in DNA methylation related to brain metastasis, we used Illumina 450K BeadChips to assess differentially methylated regions in melanocytes, primary melanomas, lymph node metastases, and brain metastases.
2013-09-19 | GSE44661 | GEO
Project description:Stephen Paget first proposed, in 1889, that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. Here, we demonstrate that exosomes released by lung-, liver- and brain-tropic tumor cells fuse preferentially with resident cells at their predicted destination, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that exosome homing to organ-specific cell types prepares the pre-metastatic niche and that treatment with exosomes derived from lung tropic models can redirect metastasis to the lung. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastasis. Whereas exosomal integrins α6β4 and α6β1 were associated with lung metastasis, exosomal integrins αvβ5 and αvβ3 were linked with liver and brain metastases, respectively. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Importantly, we demonstrate that exosome uptake activates a cell-specific subset of S100 family genes, known to support cell migration and niche formation. Finally, our clinical data indicate that integrin-expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. Education of human von Kupffer cells in vitro with human pancreatic cancer exosomes
2015-06-17 | E-GEOD-68919 | biostudies-arrayexpress
Project description:Brain metastases are critical for outcomes and quality of life in almost 50% of oncological patients, generally associated with a poor short-term prognosis. Early or preventive diagnosis of this complication represents an unmet need. There is a necessity of discovering new biomarkers that could aid to predict disease outcome. In this study, we analyzed plasma circulating extracellular vesicles (EVs) from a cohort of 92 patients with different solid tumors (lung, breast, kidney cancer and melanoma) and found that newly diagnosed patients with brain metastases presented lower number of circulating particles and a higher protein concentration in small extracellular vesicles (sEVs) compared to patients without brain metastases and healthy controls. Out of all groups analyzed, melanoma patients with brain metastases presented decreased STAT3 activation and increased PD-L1 levels in circulating sEVs compared to patients without central nervous system metastases. The data presented in this work suggest that circulating sEVs may represent the immunosuppressive status of newly diagnosed brain metastases characterized by the reduced phospho-STAT3 (pSTAT3) and increased PD-L1, although the origin of these molecules found in circulating sEVs remains to be uncovered.
2022-05-08 | PXD032767 | Pride