Oxidative phosphorylation promotes primary melanoma invasion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA602818 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10956566_1.fastq.gz | Fastqsanger.gz | |||
| SRR10956566_2.fastq.gz | Fastqsanger.gz | |||
| SRR10956567_1.fastq.gz | Fastqsanger.gz | |||
| SRR10956567_2.fastq.gz | Fastqsanger.gz | |||
| SRR10956568_1.fastq.gz | Fastqsanger.gz |
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Project description:Dermal invasion is a hallmark of malignant melanoma. The molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, whereas the early progression of non-invasive primary melanoma to an invasive state is not well understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase 1 (RSK1) drives tumor invasion. Transcriptomic analysis of RSK1-activated tumors identified metabolic changes, including upregulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1a has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens we show that PGC1a protein expression is positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species (ROS) scavenger SCARA3. PGC1a depletion modulates cellular processes associated with primary melanoma growth and invasion, including oxidative stress. Our results support a role for PGC1a in mediating glutamine-driven OXPHOS to facilitate the invasive growth of primary melanoma.
2020-01-24 | GSE144117 | GEO
Project description:Dermal invasion is a hallmark of malignant melanoma. Although the molecular alterations that drive the progression of primary melanoma to metastatic disease have been studied extensively, the early progression of noninvasive primary melanoma to an invasive state is poorly understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase A1 drives tumor invasion. Transcriptomic analysis of ribosomal protein S6 kinase A1-activated tumors identified metabolic changes, including up-regulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator activated receptor γ coactivator (PGC)-1α, has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens, PGC1α protein expression was found to be positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species scavenger receptor class A member 3. PGC1α depletion modulated cellular processes associated with primary melanoma growth and invasion, including oxidative stress. These results support a role for PGC1α in mediating glutamine-driven oxidative phosphorylation to facilitate the invasive growth of primary melanoma.
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Project description:Local invasion is a critical early step in metastatic cancer. This study investigated the invasion mechanisms of primary (IGR39) and metastatic (IGR37) melanoma cells at the single-cell level using single-probe single-cell mass spectrometry (SCMS). We detected 166 of 228 metabolites in IGR39 and 168 of 172 in IGR37.
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Project description:Local invasion is a critical early step in metastatic cancer. This study investigated the invasion mechanisms of primary (IGR39) and metastatic (IGR37) melanoma cells at the single-cell level using single-probe single-cell mass spectrometry (SCMS). We detected 166 of 228 metabolites in IGR39 and 168 of 172 in IGR37.
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Project description:Background: Melanoma brain metastases (MBM) continues to be a significant clinical problem with limited treatment options. Highly invasive melanoma cells migrate along the vasculature and perivascular cells may contribute to residual disease and recurrence. PTEN loss and hyperactivation of AKT occur in MBM; however, a role for PTEN/AKT in perivascular invasion has not been described. Methods: We used in vivo intracranial injections of murine melanoma and bulk RNA sequencing of melanoma cells co-cultured with brain endothelial cells (brECs) to investigate brain colonization and perivascular invasion. Results: We found that PTEN-null melanoma cells were highly efficient at colonizing the perivascular niche relative to PTEN-expressing counterparts. PTEN re-expression (PTEN-RE) in melanoma significantly reduced brain colonization and migration along the vasculature. We hypothesized this phenotype was mediated through vascular-induced TGFβ secretion, which drives AKT phosphorylation. Disabling TGFβ signaling in melanoma cells reduced colonization and perivascular invasion; however, introduction of constitutively-active myristolated-AKT (myrAKT) restored overall tumor size but not perivascular invasion. Conclusions: PTEN loss facilitates perivascular brain colonization and invasion of melanoma. TGFβ-AKT signaling partially contributes to this phenotype, but further studies are needed to determine the complementary mechanisms that enable melanoma cells to both survive and spread along the brain vasculature.
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Project description:Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis
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Project description:Melanoma is a common type of cancer, and metastasis remains the leading cause for mortality in melanoma patients. In this study, we utilized an unbiased mass spectrometry-based quantitative proteomic method to assess, at the global proteome scale, differential protein expression in a matched pair of primary/metastatic melanoma cell lines derived from the same patient, i.e. WM-115/WM-266-4. We found that TBC1D7 is overexpressed in metastatic (WM-266-4) relative to primary (WM-115) melanoma cells. We also observed that elevated expression of TBC1D7 promotes melanoma metastasis in vitro. Bioinformatic analyses of The Cancer Genome Atlas (TCGA) data suggested that higher mRNA expression levels of TBC1D7 predict poorer survival in melanoma patients. Furthermore, we showed that TBC1D7 promotes invasion of cultured melanoma cells in vitro, at least in part, through modulating the expression levels and activities of matrix metalloproteinases 2 and 9 (MMP2 and MMP9). Together, the results from the present study support TBC1D7 as a potential driver for melanoma metastasis.
2022-08-15 | PXD014368 | Pride
Project description:Clinical and genomic evidence support the view that the metastatic potential of a primary tumor may be dictated by transforming events acquired early in the tumorigenic process. It has been proposed that the presence of such pro-metastatic events in early-stage tumors reflects their additional capability to function as oncogenes. Here, to test this ‘deterministic’ hypothesis and identify potential pro-metastasis oncogenes, we adopted a comparative oncogenomics-guided functional genetic screening strategy involving (i) global transcriptomic data from two genetically engineered mouse models of melanoma with contrasting metastatic potential, (ii) genomic and transcriptomic profiles of human primary and metastatic melanoma and (iii) an invasion screen in TERT-immortalized human melanocytes and melanoma cells in vitro as well as (iv) evidence of expression selection in human melanoma tissues. This integrated effort led to the identification of 6 genes that are both potently pro-invasive and oncogenic. Further, we show that one such pro-invasion oncogene, ACP5, can confer spontaneous metastasis in vivo, engages a key pathway governing metastasis and is prognostic in human primary melanomas. The tetracycline-inducible MET-driven mouse (iMet) model (Tyr-rtTA;Tet-Met;Ink4a/Arf-/-) was constructed similar to the previously described iHRAS* model (Tyr-rtTA;Tet-HRASV12G;Ink4a/Arf-/-). RNA from cutaneous melanomas derived from iMet (n=6) or iHRAS* (n=6) models were profiled on Affymetrix M430A_2 chips and resultant transcriptomes were compared to generate a phenotype-based (metastatic capable or not) differentially expressed gene list. Cross-species triangulation to human gene expression and copy number aberrations was based on ortholog mapping.
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