Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA505778 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8197250_1.fastq.gz | Fastqsanger.gz | |||
| SRR8197250_2.fastq.gz | Fastqsanger.gz | |||
| SRR8197251_1.fastq.gz | Fastqsanger.gz | |||
| SRR8197251_2.fastq.gz | Fastqsanger.gz | |||
| SRR8197252_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
Similar Datasets
Project description:To Study the role of mutant Braf V600E and ERK dependent phosphorylation of TFEB in regulation of autophagy and lysosome biogenesis in the context of melanoma growth and metastasis, we used whole geneome RNA-seq to study role TFEB mediated BRAFV600E autophagy regulation.
2019-03-21 | GSE122614 | GEO
Project description:Autophagy maintains homeostasis and is induced upon stress. Yet, its mechanistic interaction with oncogenic signaling remains elusive. Here, we show that in BRAFV600E-melanoma, autophagy is induced by BRAF inhibitor (BRAFi), as part of a transcriptional program coordinating lysosome biogenesis/function, mediated by the TFEB transcription factor. TFEB is phosphorylated and thus inactivated by BRAFV600E via its downstream ERK independently of mTORC1. BRAFi disrupts TFEB phosphorylation, allowing its nuclear translocation, which is synergized by increased phosphorylation/inactivation of the ZKSCAN3 transcriptional repressor by JNK2/p38-MAPK. Blockade of BRAFi-induced transcriptional activation of autophagy-lysosomal function in melanoma xenografts causes enhanced tumor progression, EMT-transdifferentiation, metastatic dissemination, and chemoresistance, which is associated with elevated TGF-β levels and enhanced TGF-β signaling. Inhibition of TGF-β signaling restores tumor differentiation and drug responsiveness in melanoma cells. Thus, the "BRAF-TFEB-autophagy-lysosome" axis represents an intrinsic regulatory pathway in BRAF-mutant melanoma, coupling BRAF signaling with TGF-β signaling to drive tumor progression and chemoresistance.
| S-EPMC6461621 | biostudies-literature
Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.
2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress
Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.
2022-01-07 | GSE193157 | GEO
Project description:Autophagy-lysosomal degradation is an evolutionarily conserved process key to cellular homeostasis, differentiation, and stress survival, which is particularly important to the pathophysiology of the cardiovascular system. What is more, both experimental and clinical observations indicate that autophagy-lysosomal degradation affects correct cardiac morphogenesis, and in particular valve development. However, it is still unclear which cells upregulate autophagy-lysosomal degradation and for which specific cellular processes it is required. Here, we introduce novel zebrafish transgenic models to visualize autophagosomes and lysosomes in vivo and to follow their temporal and cellular localization in the larval heart. This allowed us to determine the kinetics of autophagosome and lysosome vesicle formation and to observe significant accumulation of lysosomal vesicles during the development of the atrioventricular and bulboventricular valves. We then addressed the functional role of lysosomal degradation in cardiovascular development using a spns1 mutant as a zebrafish model of lysosomal impairment. We found that spns1 mutants displayed morphologically and functionally abnormal heart development, including abnormal endocardial organization, impaired cardiac valve formation and high incidence of retrograde blood flow. Single-nuclear transcriptome analysis revealed endocardial-specific differences in the expression of lysosome-related genes and alterations of notch1 signaling in the mutant larval heart. Further, endocardial-specific overexpression of spns1 and notch1 rescued features of valve formation and function as well as overall cardiac morphogenesis. Altogether, our study provides an improved description of the autophagy and lysosomal events that take place during zebrafish heart development and reveals a cell-autonomous role of lysosomal processing during cardiac valve formation upstream of notch1 signaling.
2024-10-25 | GSE246850 | GEO
Project description:OSCC is a common cancer of the head and neck. Despite ongoing efforts, there remains a dearth of targeted drugs capable of effectively inhibiting OSCC growth. As the earliest discovered proto-oncogene in the SRSF family, targeted inhibition of SRSF1 plays an important role in tumor suppression. However, a comprehensive report on the expression, function, and mechanism of SRSF1 in OSCC has yet to be presented. This study retrospectively analyzed clinical samples from OSCC patients and discovered a significant correlation between the SRSF1 expression level and poor prognosis. In vitro experimentation demonstrated that SRSF1 knockdown inhibited OSCC growth, survival, lysosomal biogenesis and autophagy. To confirm the significance of lysosomal function and autophagy in the regulation of OSCC growth by SRSF1, cell rescue models were constructed. The aforementioned findings were subsequently validated in xenograft models. Ultimately, targeted knockdown of SRSF1 was found to significantly suppress OSCC growth by impeding lysosomal biogenesis and autophagy.
2023-12-01 | GSE244710 | GEO
Project description:Glioblastoma (GBM) is a devastating disease and the most common primary brain malignancy of adults with a median survival barely exceeding one year. Recent findings suggest that the antipsychotic drug pimozide triggers an autophagy-dependent, lysosomal type of cell death in GBM cells with possible implications for GBM therapy. One oncoprotein that is often overactivated in these tumors and associated with a particularly dismal prognosis is Signal Transducer and Activator of Transcription 3 (STAT3). Here, we used isogenic human GBM knockout cell lines, advanced fluorescence microscopy, transcriptomic analysis and FACS-based assessment of cell viability to show that STAT3 has an underappreciated, context-dependent role in drug-induced cell death. Specifically, we demonstrate that depletion of STAT3 significantly enhances cell survival after treatment with pimozide, suggesting that STAT3 confers a particular vulnerability to GBM. Furthermore, we show that active STAT3 has no major influence on the early steps of the autophagy pathway, but exacerbates drug-induced lysosomal membrane permeabilisation (LMP) and release of cathepsins into the cytosol. Collectively, our findings support the concept of exploiting the pro-death functions of autophagy and LMP for GBM therapy and to further determine whether STAT3 can be employed as a treatment predictor for highly apoptosis-resistant, but autophagy-proficient cancers.
2022-01-13 | GSE162429 | GEO
Project description:Cisplatin (CDDP) is a widely used agent in the treatment of neuroblastoma. Unfortunately, the development of acquired chemoresistance limits its clinical use. To gain a detailed understanding of the mechanisms underlying the development of such chemoresistance, we comparatively analysed established cisplatin-resistant neuroblastoma cell line (UKF-NB- 4CDDP) and its sensitive counterpart (UKF-NB-4). We confirmed the decreased sensitivity of tested cells to cisplatin and identified a cross-resistance to carboplatin and oxaliplatin. Among the proteins responsible for UKF-NB-4CDDP chemoresistance, ion channels transport family proteins, ABC superfamily proteins, SLC-mediated trans-membrane transporters, proteasome complex subunits and V-ATPases were identified. Moreover, we detected markedly higher proteasome activity in UKF-NB-4CDDP cells and a remarkable lysosomal enrichment that can be inhibited by bafilomycin A to sensitize UKF-NB-4CDDP to CDDP. Our results indicate that lysosomal sequestration and proteasome activity may be one of key mechanisms responsible for intrinsic chemoresistance of neuroblastoma to CDDP.
2019-01-02 | PXD012132 | Pride
Project description:The gastrointestinal tract may be a site of origin for α-synuclein (α-syn) pathology in idiopathic Parkinson’s disease (PD), and an abundance of aggregated α-syn has recently been demonstrated in both the healthy and PD appendix. However, the molecular changes that enable gut α-syn aggregates to contribute to the development and progression of PD remain unclear. Here, our deep-sequencing of DNA methylation changes at 521 autophagy-lysosomal pathway (ALP) genes in the human appendix and brain in PD and healthy controls indicates a pattern of widespread hypermethylation in the PD appendix that is recapitulated in the PD brain. There is significant overlap in the individual ALP genes affected across the PD appendix and brain, with lysosomal genes specifically downregulated in both regions. Healthy epigenetic aging, which involves a hypermethylation of macroautophagy and selective autophagy genes in the appendix and brain, is disrupted in both areas in PD. In mice, DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by the presence of α-syn pathology. DNA methylation changes at ALP genes induced by α-synucleinopathy are significantly associated with the ALP abnormalities observed in the PD appendix, specifically involving lysosomal genes. Our work, which constitutes an in-depth, unbiased investigation of epigenetic changes in the ALP of the PD gut and brain, identifies the epigenetic misregulation of the ALP, especially a downregulation of lysosomal genes, as a potential culprit for the initiation and spread of α-syn pathology in idiopathic PD.
2021-02-01 | GSE135743 | GEO
Project description:The gastrointestinal tract may be a site of origin for α-synuclein (α-syn) pathology in idiopathic Parkinson’s disease (PD), and an abundance of aggregated α-syn has recently been demonstrated in both the healthy and PD appendix. However, the molecular changes that enable gut α-syn aggregates to contribute to the development and progression of PD remain unclear. Here, our deep-sequencing of DNA methylation changes at 521 autophagy-lysosomal pathway (ALP) genes in the human appendix and brain in PD and healthy controls indicates a pattern of widespread hypermethylation in the PD appendix that is recapitulated in the PD brain. There is significant overlap in the individual ALP genes affected across the PD appendix and brain, with lysosomal genes specifically downregulated in both regions. Healthy epigenetic aging, which involves a hypermethylation of macroautophagy and selective autophagy genes in the appendix and brain, is disrupted in both areas in PD. In mice, DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by the presence of α-syn pathology. DNA methylation changes at ALP genes induced by α-synucleinopathy are significantly associated with the ALP abnormalities observed in the PD appendix, specifically involving lysosomal genes. Our work, which constitutes an in-depth, unbiased investigation of epigenetic changes in the ALP of the PD gut and brain, identifies the epigenetic misregulation of the ALP, especially a downregulation of lysosomal genes, as a potential culprit for the initiation and spread of α-syn pathology in idiopathic PD.
2021-03-01 | GSE135750 | GEO