Heterogeneity of tyrosine-based melanin anabolism regulates pulmonary and cerebral organotropic colonization microenvironment of melanoma cells
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ABSTRACT:
PROVIDER: PRJNA790855 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17279205_1.fastq.gz | Fastqsanger.gz | |||
| SRR17279205_2.fastq.gz | Fastqsanger.gz | |||
| SRR17279206_1.fastq.gz | Fastqsanger.gz | |||
| SRR17279206_2.fastq.gz | Fastqsanger.gz | |||
| SRR17279207_1.fastq.gz | Fastqsanger.gz |
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Project description:Dietary tyrosine regulating melanoma progression has been well-recognized. However, whether tyrosine-based melanin anabolism contributes to pulmonary and cerebral organotropic colonization of melanoma remains elusive. Furthermore, how to inhibit multi-organ metastasis by interfering tyrosinase activity of melanoma cells and function of immunocytes needs to be designed and validated. Patients derived melanoma cells and mouse B16 melanoma cells with different pigment were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression were monitored, and tyrosine-based melanin synthesis ability of melanoma cells derived from multi-organ were detected. Additionally, we also adopted the RNA-seq, flowcytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to design therapeutic strategies. B16 melanoma cells with high activity of tyrosinase and sensitivity of tyrosine utilization for melanin synthesis (Tyr-H cells) easily colonized in the lung, while B16 melanoma cells without above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to build up the pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excess melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of tyrosinase activity (2-Ethoxybenzamide or hydroquinone), together with inhibitors to phagocytosis (GSK343) or chemotaxis (SB225002) suppress organotropic colonization and significantly improve the survival of immune checkpoint blockade (PD1 antibody) treated melanoma bearing mice. The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing strategies to combat melanoma and prevent their metastasis.
2022-03-15 | GSE191289 | GEO
Project description:Background: Dietary tyrosine regulating melanoma progression has been well-recognized. However, whether tyrosine-based melanin anabolism contributes to pulmonary and cerebral organotropic colonization of melanoma remains elusive. Furthermore, approaches based on targeting tyrosinase activity to inhibiting multi-organ metastasis of melanoma cells need to be designed and validated. Methods: Patients derived melanoma cells and mouse B16 melanoma cells with different pigmentation were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression was monitored, and tyrosine-based melanin synthesis of melanoma cells derived from multi-organ was determined. Additionally, we also adopted RNA-seq, flow cytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to validate designed therapeutic strategies. Results: B16 melanoma cells with high activity of tyrosinase and sensitivity of tyrosine utilization for melanin synthesis (Tyr-H cells) easily colonized in the lung, while B16 melanoma cells lacking above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to establish pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excessive melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of tyrosinase activity (2-Ethoxybenzamide or hydroquinone) in combination with inhibitors of phagocytosis (GSK343) or chemotaxis (SB225002) suppressed organotropic colonization and significantly improved the survival of melanoma- bearing mice treated with immune checkpoint blockade (PD1 antibody). Conclusions: The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing new strategies to combat melanoma.
| S-EPMC8899568 | biostudies-literature
Project description:During the long history of chicken domestication, eyelid color, like skin color and shank color, has been one of the unique physical traits of Chinese indigenous chickens that influence consumer behavior. In China, the Lindian chicken, which has colored feathers, is renowned for the appetizing flavor of its meat and eggs, and its eyelid colors varies from deep to light shades, including black, gray, red, and light yellow. To identify the genes controlling eyelid pigmentation, the expression profiles of black and light-yellow eyelids of Lindian chickens were analyzed with transcriptome sequencing. We detected 13,466 genes expressed in the eyelids, among which 14 were differentially expressed. A KEGG pathway analysis showed that tyrosine metabolism and melanogenesis genes were significantly enriched among these DEGs (corrected P < 0.05). Therefore, we infer that melanin metabolism is one of main factors affecting Lindian chicken eyelid pigmentation. In summary, we have identified the melanin genes responsible for eyelid pigmentation of the Lindian chicken, and also provide a valuable resource for the future study of the physical traits of chickens.
2018-10-25 | GSE101452 | GEO
Project description:Melanin is an antioxidant polyphenol pigment, which is required for the pathogenicity of many human and plant fungal pathogens. Nevertheless, its comprehensive regulatory mechanism still remain elusive. In this study, we systematically analyzed melanin-regulating signaling pathways in Cryptococcus neoformans. Here we identified four core melanin-regulating TFs, Bzp4, Usv101, Mbs1, and Hob1, which are required for induction of the laccase gene (LAC1). Bzp4, Usv101 and Mbs1 independently regulate LAC1 induction while Hob1 controls Bzp4 and Usv101 expression. Both Bzp4 and Usv101 are translocated from the cytoplasm into the nucleus upon nutrient starved condition, while Mbs1 is constitutively localized in the nucleus. Notably, the cAMP pathway is not involved in regulation of the four TFs, while the HOG pathway negatively regulates induction of BZP4 and LAC1. As potential kinases upstream of the core TFs, we identified the nine core kinases, whose deletion leads to defective melanin production and LAC1 induction. Deletion of GSK3 or KIC1 abolishes induction of LAC1 and BZP4, and also perturbs nuclear translocation of Bzp4. Notably, Gsk3 also regulates the expression of HOB1, USV101, and MBS1, indicating that it is a critical melanin-regulating kinase. Finally, the RNA-sequencing based transcriptome analysis of the wild-type and bzp4Δ, usv101Δ, hob1Δ, and mbs1Δ strains under nutrient rich and starved conditions reveals that the core melanin-regulating TFs govern redundant and distinct classes of genes, which are involved in a variety of biological processes.
2019-05-30 | GSE131891 | GEO
Project description:Feather coloration is one of the most extraordinary examples of phenotypic diversity. This diversity results both from the variation in hue as well as from the presence/absence of pigment in distinct feather regions. The mechanisms that drive presence/absence of pigmentation in feathers are not yet fully understood. Here we characterize the gene expression profiles associated with differential melanin pigmentation in Dark-eyed junco (Junco hyemalis) tails, a social feather ornament used in courtship and male-male competition. Junco tail feathers contain both white apigmented regions as well as dark melanin-pigmented regions. We compared the transcriptome-wide gene expression in developing white and dark regions of tail feathers to understand the regulatory pathways that may regulate the development of this feather ornament. We show that both white and dark feathers express melanocyte markers, indicating that white feathers contain cells capable of producing pigment. However, only dark cells express genes associated with melanin synthesis. We identify differences in expression of genes that may regulate melanocyte activation in dark feathers. Future studies should experimentally test the role of these genes in driving differences in feather pigmentation.
2023-01-08 | GSE167085 | GEO
Project description:Alternaria brassicicola is a successful saprophyte and necrotrophic plant pathogen. Several A. brassicicola genes have been characterized as virulence factors affecting pathogenesis of Brassica species. To study regulatory mechanisms of pathogenesis, we mined 421 genes in silico encoding putative transcription factors in a machine-annotated, draft genome sequence of A. brassicicola. Targeted gene disruption mutants for 114 of the genes with proteins predicted to contain at least one putative zinc-finger domain were produced and functionally analyzed. Six of these genes were associated with pathogenesis. Disruption mutants corresponding to five of the genes were ≥50% less virulent than the wild type. Unexpectedly, the mutants of one gene (designated Amr1) were 100% more virulent. Amr1 is a homolog of Cmr1, a transcription factor previously found to regulate melanin biosynthesis in several fungi. Gene deletion mutants (Δamr1) were created and their phenotypes characterized. The Δamr1 mutants utilized pectin as a carbon source more efficiently than the wild type, were melanin-deficient, and more sensitive to UV light and glucanase digestion. The Amr1 protein was localized in the nuclei of hyphae and in highly melanized conidia during the late stage of plant pathogenesis. RNA-seq analysis revealed that three genes in the melanin biosynthesis pathway, along with the deleted Amr1 gene, were not expressed in the mutants. In contrast, many hydrolytic enzyme-coding genes were expressed at much higher levels in the mutants than in the wild type during pathogenesis. The results of this study suggested that only a small number of transcription factors with zinc finger domains are needed to maintain strong virulence. Furthermore, a gene important for survival in nature negatively affected virulence, probably by less efficient use of pectin. We speculate that the functions of the Amr1 gene are important to the success of A. brassicicola as a competitive saprophyte and plant parasite gene expression profile comparisons between wild type and a transcription factor mutant during the late stage of host infection
2013-02-19 | E-GEOD-36781 | biostudies-arrayexpress
Project description:The goals of this study were to investigate whether two anesthesia regimens, with and without N2O, and bacterial colonization influence respiratory complications after major abdominal surgery for cancer.
| 2309559 | ecrin-mdr-crc
Project description:Tyrosine Kinase Inhibitor Cardiotoxicity
| PRJNA352077 | ENA
Project description:A. flavus keratitis is one of the predominant fungal infections affecting the tropical parts of the world. Melanin is a virulence factor in numerous pathogenic fungi and the melanin layer maintains the cell wall structure and provides chemical and physical protection to the organism. However, the molecular and biological mechanisms modulating melanin-mediated host-pathogen interaction in A. flavus keratitis are not well understood. This work aimed to compare the morphology, surface proteome profile and virulence of melanized and non-melanized conidia of A. flavus. An environmental isolate and two clinical isolates were included in this study. L-DOPA melanin pathway-specific inhibitor kojic acid (KA) as used to prepare non-melanized conidia. Conidial surface proteins were extracted using 100% formic acid at 0 ºC and the extracted proteins were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE). Formic acid extracts were analyzed in an Orbitrap Velos pro-mass spectrometer. Conidial surface morphology difference was examined using scanning electron microscopy (SEM). Furthermore, lactophenol and calcofluor staining were performed to check the morphology and staining efficiency of melanized conidia (MC) and non-melanized conidia (NMC). A Galleria mellonella insect model was used to examine the virulence efficiency of MC and NMC. Kojic acid treatment inhibited melanin synthesis in A. flavus and the conidial surface protein profile was significantly different in kojic acid-treated non-melanized conidia. Several cell wall-associated proteins and proteins responsible for oxidative stress, carbohydrate, and chitin metabolic pathway were found only in the formic acid extracts of NMC. SEM analysis showed the conidial surface morphology difference between the NMC and MC indicating the role of melanin in the structural integrity of the conidial cell wall. The levels of calcofluor staining efficiency were different, but there was no microscopic morphology difference in lactophenol cotton blue staining of MC and NMC. Evaluation of virulence of MC and NMC in G. mellonella model showed NMC was less virulent compared to MC . Our results showed that the integrity of the conidial surface is controlled by the melanin layer. The alteration in the surface protein profile indicated that many surface proteins are masked by the melanin layer and hence melanin can modulate the host response by preventing the exposure of fungal proteins to the host immune defense system. G. mellonella in vivo virulence assay also confirmed that the non-melanized conidia were susceptible to host defense as in other Aspergillus pathogens.
2024-05-23 | PXD037707 | Pride
Project description:The use of patient-derived primary cell cultures in cancer preclinical assays, including drug screens and genotoxic studies, has increased in recent years. However, their translational value is constrained by several limitations, including variability that can be caused by the culture conditions. Here, we show that the medium composition commonly used to propagate primary melanoma cultures has limited their representability of their tumor of origin, their cellular plasticity and modified their sensitivity to therapy. We established and compared cultures from different melanoma patients propagated in parallel in low-tyrosine (Ham’s F10) or, in high-tyrosine (Ham’s F10 supplemented with tyrosine, RPMI/DMEM) media. Tyrosine is the precursor of melanin biosynthesis, a process particularly active in differentiated melanocytes and melanoma cells. Unexpectedly, we found that the high tyrosine concentrations promoted an early phenotypic drift towards either a mesenchymal-like or senescence-like phenotype, and prevented the establishment of cultures of melanoma cells harboring differentiated features, which we show are frequently present in human clinical biopsies. Moreover, the invasive phenotype emerging in these culture conditions appeared irreversible and, as expected, associated with intrinsic resistance to MAPKi. In sharp contrast, differentiated melanoma cell cultures retained their phenotypes upon propagation in low-tyrosine medium, and importantly their phenotypic plasticity, a key hallmark of melanoma cells. Our findings underline the importance of culturing melanoma cells in low-tyrosine-containing medium in order to preserve their phenotypic identity of origin and cellular plasticity.
2021-11-03 | GSE171456 | GEO