Paired biopsies melanoma
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Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes. Total RNA was obtained from fresh-frozen melanoma tumour samples from patients before commencing treatment with dabrafenib or vemurafenib and at time of tumour progression.
2014-02-19 | E-GEOD-50509 | biostudies-arrayexpress
Project description:The BRAFV600E mutant melanoma cell line M14 responds to the BRAF inhibitor vemurafenib, however, the differences in response between individual cells are underlying resistance. To highlight the underlying mechanisms, we performed treatment of M14 cells with vemurafenib, followed by Drop-seq. We were able to clearly distinguish cells that were treated with the drug from untreated cells, and we discovered different cell populations within the treated cells, likely reflecting heterogeneity of drug resistant cells. We were able to identify specific biomarkers, as preferentially expressed genes, for each cell population. The results of our study will address preexisting and acquired drug resistance that limits clinical usefulness of targeted strategies.
2020-12-19 | GSE134838 | GEO
Project description:About 50% of colorectal cancer patients develop liver metastases. Patients with metastatic colorectal cancer have 5-year survival rates below 20% despite new therapeutic regimens. Tumor heterogeneity has been linked with poor clinical outcome, but was so far mainly studied via bulk genomic analyses. In this study we performed spatial proteomics via MALDI mass spectrometry imaging on six patient matched CRC primary tumor and liver metastases to characterize interpatient, intertumor and intratumor hetereogeneity. We found several peptide features that were enriched in vital tumor areas of primary tumors and liver metastasis and tentatively derived from tumor cell specific proteins such as annexin A4 and prelamin A/C. Liver metastases of colorectal cancer showed higher heterogeneity between patients than primary tumors while within patients both entities show similar intratumor heterogeneity sometimes organized in zonal pattern. Together our findings give new insights into the spatial proteomic heterogeneity of primary CRC and patient matched liver metastases.
2023-02-17 | PXD039409 | Pride
Project description:In order to identify mechanisms of melanoma treatment resistance, we applied micorofluidic scRNA-Seq to the transcripomes of a total of about 31,000 single cells obtained form A375 melanoma cell line untreated/sensitive or treated with BRAF inhibitor vemurafenib, either alone or in combination with MEK1 inihibitor cobimetinib or trametinib. Analysis by dimensionality reduction software tSNE and SOM identified a clonal heterogeneity clearly seperating all 4 possible treatment conditions.
2021-01-16 | GSE164897 | GEO
Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma.
2014-05-20 | GSE42872 | GEO
Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma. BRAFV600E A375 human melanoma cells were treated with vehicle (0.1% DMSO) or 10 uM vemurafenib for 24 h after which total RNA was extracted. Cells were prepared and RNA was extracted in 3 separate batches (three different cell stocks on three separate days) providing three independent replicates (n=3). Paired replicates (prepared from the same stock of cells on the same day) are denoted by A, B and C.
2014-05-20 | E-GEOD-42872 | biostudies-arrayexpress
Project description:Single-cell assessment of bone marrow metastases is essential to decipher the entire spectrum of tumor heterogeneity in solid cancers with bone marrow involvement. We used multi-epitope-ligand cartography (MELC) to spatially profile 20 biomarkers in 35,000 disseminated tumor cells (DTCs), hematopoietic and mesenchymal cells from eight neuroblastoma bone marrow metastases. We developed DeepFLEX, a single-cell image analysis pipeline for MELC data that combines deep learning-based cell and nucleus segmentation and overcomes frequent challenges of multiplex imaging methods. Comparisons of cell type proportions between samples indicated that microenvironmental changes in the bone marrow are associated with tumor cell infiltration and therapy response. Hierarchical clustering of DTCs revealed multiple phenotypes with highly diverse expression of markers such as FAIM2, which we propose as a complementary marker to capture DTC heterogeneity in neuroblastoma. This single-cell atlas is an important step towards a deeper understanding of DTCs and their interactions with the bone marrow niche.
2021-09-07 | GSE172184 | GEO
Project description:Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. In this study, we used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. We found that β-sitosterol attenuated melanoma cell growth in vitro and significantly inhibited brain metastasis in vivo. Large-scale phosphoproteomic and in silico analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiration and respiratory capacity in melanoma cells, mediated by a selective inhibition of mitochondrial complex I. This led to increased oxidative stress and apoptosis. Notably, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. Based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising candidate for drug repurposing in patients with, or at risk for, melanoma brain metastases.
2019-04-06 | GSE100066 | GEO
Project description:To explore the characteristics of senescent melanoma cells induced by vemurafenib or cisplatin, melanoma A375 cells were treated with vemurafenib and cisplatin, respectively. The senescent phenotypes were verified by β-gal staining, EdU assay, cell morphology and the senescence-related pathways. RNA-seq was performed to explore the differentially expressed genes in the senescent cells induced by vemurafenib or cisplatin.
2023-07-07 | GSE209769 | GEO
Project description:Immunotherapy and targeted therapy dramatically changed the treatment of metastatic melanoma. Yet, many patients do not respond to these treatments and improve the understanding of response and resistance is an urgent need. Thus, we utilized mass spectrometry-based proteomic analysis of 185 metastatic melanoma samples. Metastases from different sites demonstrate differences in cellular processes such as immune, metabolism, translation and proliferation. Complementary epidemiology analysis uncovers prognosis variance between different metastases locations after treated with anti-PD1. Examination of lung melanoma metastases reveals clinical and molecular heterogeneity that mainly reflected in immune-related processes. Analysis of BRAF mutation status and prior treatments with MAPK inhibitors also indicate differences in immune and metabolic processes and suggest a molecular basis for the combination of immunotherapy and targeted therapy. These results shed new light into biology and therapeutic resistant mechanisms and the pathogenesis of metastatic melanoma.
2020-12-23 | PXD020618 | Pride