A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1165729 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Innate factors such as β-defensins may exhibit anti-cancer functions, serving as a first line of defense against incipient or dormant cancer cells. In previous studies, our lab demonstrated that hemoglobin-derived factors such as the hemoglobin beta chain or an alpha/beta heterodimer of hemoglobin trigger apoptosis and necrosis in neuroblastoma and brain-metastasizing melanoma cells, respectively. In addition to its cytotoxic function, the alpha/beta hemoglobin dimer downregulated the expression of proteins such as BRD4 and IRS2, which perform essential functions in tumorigenesis and cancer progression. In the present study, we proved the concept, raised for the first time in this study, that in addition to their anti-cancer functions, innate resistance factors could serve as pathfinders to identify theranostic targets on progressing cancer cells.
2024-10-03 | GSE278118 | GEO
Project description:Metastatic (as well as tumor) microenvironments contain both cancer-promoting as well as cancer restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung-derived antimetastatic factor. In the present study, exploring mechanisms leading to melanoma brain metastasis, we discovered that brain-derived factors restrain proliferation and induce apoptosis and necrosis of brain-metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that performs these anti-metastatic functions. Neither the alpha nor the beta subunit alone were inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer-induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer-treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins playing crucial roles in cancer cell sustainability and progression.
2023-03-08 | GSE225459 | GEO
Project description:The present study deals with functional interactions of cutaneous and brain-metastasizing human melanoma cells with brain-derived molecules. In this study we employed the unique melanoma xenograft model developed by Izraely and described in Int J Cancer. 2011 Oct 25. doi: 10.1002/ijc.27324. The present study aims to determine if brain-derived soluble factors regulate malignancy-associated functions of cutaneous and brain-metastasizing melanoma cells and identify which functions are regulated by such factors. The working hypothesis of this study is that the interactions between the brain microenvironment and melanoma cells determine metastasis formation at this organ site. The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential pre-requisite for the development of effective targeted therapy for melanoma brain metastasis. We assessed the effects of soluble factors present in supernatants of short-term cultures of normal mouse brain (referred here after as brain-derived soluble factors) on several characteristics linked to melanoma brain metastasis. It was found that brain-derived soluble factors affect differentially cutaneous and brain-metastasizing melanoma cells variants in-vitro. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. Brain-derived soluble factors enhanced migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors up-regulated the expression of the chemokine receptor CCR4 in both cutaneous and brain metastasizing melanoma cells. It is not unlikely that CCR4 ligands expressed in the brain interact with the CCR4-expressing melanoma cells thereby directing them to the brain. Brain-derived soluble factors enhanced the transmigration, across human brain endothelial cells of cutaneous but not of brain metastasizing melanoma variants. This activity could promote the capacity of the cutaneous cells to metastasize to the brain. 4 Samples (arrays) were analyzed. There is 1 replicate for each variant and each treatment. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with p≤5% and a fold-change difference of ≥2 or <-2 were selected.
2012-01-11 | E-GEOD-34970 | biostudies-arrayexpress
Project description:The present study deals with functional interactions of cutaneous and brain-metastasizing human melanoma cells with brain-derived molecules. In this study we employed the unique melanoma xenograft model developed by Izraely and described in Int J Cancer. 2011 Oct 25. doi: 10.1002/ijc.27324. The present study aims to determine if brain-derived soluble factors regulate malignancy-associated functions of cutaneous and brain-metastasizing melanoma cells and identify which functions are regulated by such factors. The working hypothesis of this study is that the interactions between the brain microenvironment and melanoma cells determine metastasis formation at this organ site. The aim of the study was to evaluate the contribution of such interactions to the formation of brain metastasis in nude mice xenografted with human melanoma cells. An insight into these interactions is an essential pre-requisite for the development of effective targeted therapy for melanoma brain metastasis. We assessed the effects of soluble factors present in supernatants of short-term cultures of normal mouse brain (referred here after as brain-derived soluble factors) on several characteristics linked to melanoma brain metastasis. It was found that brain-derived soluble factors affect differentially cutaneous and brain-metastasizing melanoma cells variants in-vitro. Such factors enhanced the viability of cutaneous melanoma cells but caused an S phase arrest followed by apoptosis of brain-metastasizing cells. Brain-derived soluble factors enhanced migration of melanoma cells metastasizing to the brain, but did not affect the migration of the cutaneous variants. Such factors up-regulated the expression of the chemokine receptor CCR4 in both cutaneous and brain metastasizing melanoma cells. It is not unlikely that CCR4 ligands expressed in the brain interact with the CCR4-expressing melanoma cells thereby directing them to the brain. Brain-derived soluble factors enhanced the transmigration, across human brain endothelial cells of cutaneous but not of brain metastasizing melanoma variants. This activity could promote the capacity of the cutaneous cells to metastasize to the brain.
2012-01-11 | GSE34970 | GEO
Project description:V600E being the most common mutation in BRAF, leads to constitutive activation of the MAPK signaling pathway. The majority of V600E BRAF positive melanoma patients treated with the BRAF inhibitor vemurafenib showed initial good clinical responses but relapsed due to acquired resistance to the drug. The aim of the present study was to identify possible biomarkers associated with the emergence of drug resistant melanoma cells. To this end we analyzed the differential gene expression of vemurafenib-sensitive and vemurafenib resistant brain and lung metastasizing melanoma cells. The major finding of this study is that the in vitro induction of vemurafenib resistance in melanoma cells is associated with an increased malignancy phenotype of these cells. Resistant cells expressed higher levels of genes coding for cancer stem cell markers (JARID1B, CD271 and Fibronectin) as well as genes involved in drug resistance (ABCG2), cell invasion and promotion of metastasis (MMP-1 and MMP-2). We also showed that drug-resistant melanoma cells adhere better to and transmigrate more efficiently through lung endothelial cells than drug-sensitive cells. The former cells also alter their microenvironment in a different manner from that of drug-sensitive cells. Biomarkers and molecular mechanisms associated with drug resistance may serve as targets for therapy of drug-resistant cancer.
2015-03-20 | GSE67088 | GEO
Project description:Road to metastasis:the TWEAK pathway as a discriminant between metastasizing and non-metastasizing thick melanomas
| PRJEB47586 | ENA
Project description:A heterodimer of α and β hemoglobin chains functions as an innate anticancer agent
| PRJNA935740 | ENA
Project description:Uveal melanoma metastases are lethal and remain incurable. Quantitative proteomic analysis of 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM) was pursued for insights into UM metastasis and protein biomarkers. The metastatic status of the pUM specimens was defined based on clinical data, survival histories, prognostic analyses, and liver histopathology. LC MS/MS iTRAQ technology, the Mascot search engine and the UniProt human database were used to identify and quantify pUM proteins relative to normal choroid excised from UM donor eyes containing metastasizing (n=6) and non-metastasizing (n=7) pUM. The determined proteomes of all 100 tumors were very similar, encompassing a total of 3935 pUM proteins. Proteins differentially expressed (DE) (n=402) between metastasizing and non-metastasizing pUM were employed in bioinformatic analyses that predicted significant differences in the immune system between metastasizing and non-metastasizing pUM. Immune proteins (n=778) identified in this study support the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM and suggest CDH1 and HLA-DPA1 as candidates for immune therapy checkpoint blockade. Prediction modeling identified 32 proteins capable of predicting with 93% discriminatory accuracy metastasizing versus non-metastasizing pUM, supporting the potential of protein-based prognostic methods for detecting UM metastasis
2021-05-15 | MSV000087437 | MassIVE
Project description:We established a model of human melanoma metastasis to identify differentially expressed genes in brain metastasis, compared to cutaneous melanoma from which they were developed. Such genes may control brain metastasis. The identification and characterization of these genes would advance the understanding of the metastatic process and may lead to new diagnostics and therapeutic approach. Brain metastases occur in almost 40% of melanoma patients. The median survival of such patients does not exceed a few months. Very little information is available on mechanisms underlying the progression of melanoma towards brain metastasis. The function, and significance of the various factors involved in melanoma progression must be deciphered using relevant models. Currently, most human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intra-cardiac administration. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, sub-dermal variants that originate from the same melanomas thus sharing a common genetic background. The brain metastasizing variants were obtained by intra-cardiac inoculation. One of the brain metastasizing variants when inoculated sub-dermally yielded spontaneous brain dormant micrometastasis. Cells from the spontaneous brain micrometastasis when removed from the brain microenvironment proliferate very well in vitro and generate tumors in the skin being the orthotopic organ site. The brain metastasis and micro-metastasis cells expressed higher levels of ANGPTL4, COX-2, MMP1, MMP2 and PRAME and lower levels of CLDN1, CYR61 and IL-6R than the cutaneous variants. These gene products may be involved in melanoma brain metastasis and may serve as novel brain metastasis biomarkers and targets for therapy. 8 Samples (arrays) were analyzed. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with pM-bM-^IM-$5% and a fold-change difference of M-bM-^IM-%1.25 or <-1.25 were selected.
2011-03-17 | E-GEOD-27980 | biostudies-arrayexpress
Project description:We established a model of human melanoma metastasis to identify differentially expressed genes in brain metastasis, compared to cutaneous melanoma from which they were developed. Such genes may control brain metastasis. The identification and characterization of these genes would advance the understanding of the metastatic process and may lead to new diagnostics and therapeutic approach. Brain metastases occur in almost 40% of melanoma patients. The median survival of such patients does not exceed a few months. Very little information is available on mechanisms underlying the progression of melanoma towards brain metastasis. The function, and significance of the various factors involved in melanoma progression must be deciphered using relevant models. Currently, most human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intra-cardiac administration. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, sub-dermal variants that originate from the same melanomas thus sharing a common genetic background. The brain metastasizing variants were obtained by intra-cardiac inoculation. One of the brain metastasizing variants when inoculated sub-dermally yielded spontaneous brain dormant micrometastasis. Cells from the spontaneous brain micrometastasis when removed from the brain microenvironment proliferate very well in vitro and generate tumors in the skin being the orthotopic organ site. The brain metastasis and micro-metastasis cells expressed higher levels of ANGPTL4, COX-2, MMP1, MMP2 and PRAME and lower levels of CLDN1, CYR61 and IL-6R than the cutaneous variants. These gene products may be involved in melanoma brain metastasis and may serve as novel brain metastasis biomarkers and targets for therapy.
2011-03-17 | GSE27980 | GEO