Molecular analysis of a case of renal cell carcinoma with t(6;11) (p21;q12) reveals a link to a lysosome-like structure
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49901 | GEO | 2013/08/16
SECONDARY ACCESSION(S): PRJNA215380
REPOSITORIES: GEO
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Project description:TFEB has been recently reported to be a key molecule for lysosomal regulation. Renal cell carcinoma (RCC) with t(6;11) (p21;q12) is known to be the only tumor in which TFEB is upregulated. Transcriptome analysis using a whole-genome expression array and pathway analysis using upregulated genes in tumor tissue revealed that the lysosome-associated pathways were significantly deregulated. Total RNA was extracted from non-tumor and tumor in patient of renal cell carcinoma with t(6;11) (p21;q12) and subjected to gene expression microarray analysis.
2013-08-16 | E-GEOD-49901 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) infects multiple lung myeloid cell subsets and persists despite innate and adaptive immune responses. However, the mechanisms allowing Mtb to evade elimination by these subsets are not fully understood. Here, we determined that four weeks post infection, after development of adaptive immune responses, CD11clo monocyte-derived lung cells termed MNC1 (mononuclear cell subset 1), harbor more live Mtb compared to alveolar macrophages (AM), neutrophils, and less permissive CD11chi MNC2. Bulk RNA-seq analysis for these subsets identified that lysosome biogenesis pathway is underexpressed in MNC1. Functional assays confirmed that Mtb-permissive MNC1 are deficient in lysosome content, lysosomal acidification, and lysosomal activity compared to AM, and have less nuclear TFEB, a master regulator of lysosome biogenesis. Mtb infection does not alter lysosome deficiency in MNC1. Instead, Mtb recruits MNC1 and MNC2 to the lungs for its spread from AM to these subsets, which depend on Mtb ESX-1 secretion system. Furthermore, nilotinib-mediated TFEB activation enhances lysosome function of primary macrophages in vitro, and MNC1 and MNC2 in vivo, improving control of Mtb infection. Our results suggest that Mtb exploits lysosome-poor monocyte-derived lung cells for persistence; targeting lysosome biogenesis may be an effective approach to host-directed therapy for tuberculosis, enabling permissive lung cells to restrict and kill Mtb through autophagy and other mechanisms.
2023-02-08 | GSE220147 | GEO
Project description:We report here 3 cases of a very rare entity of renal cell carcinomas (RCCs) that present an amplification of TFEB gene. This amplification, as well as translocation t(6;11) involving TFEB and MALAT1, leads to un overexpression of TFEB protein and seems to be a pejorative prognosis factor among TFEB RCCs
2015-10-14 | GSE73979 | GEO
Project description:The mechanisms that govern organelle remodeling remain poorly defined. Lysosomes degrade cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, lysosomes are a kingpin organelle since they are essential to kill pathogens and process and present antigens. During phagocyte activation, lysosomes undergo a striking reorganization, changing from dozens of globular structures to a tubular network, in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that lysosomes undergo a remarkable expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Lysosome expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation of mRNAs encoding key lysosomal proteins. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for lysosome expansion that relies on mTORC1-dependent enhanced translation of mRNAs to boost protein synthesis and lysosome biogenesis in response to an infection signal.
2020-01-07 | GSE136470 | GEO
Project description:Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research
2024-01-04 | GSE252047 | GEO
Project description:The activation of cellular quality control pathways to maintain metabolic homeostasis and mitigate diverse cellular stresses is emerging as a critical growth and survival mechanism in many cancers. Autophagy, a highly conserved cellular self-degradative process, is a key player in the initiation and maintenance of pancreatic ductal adenocarcinoma (PDA). However, the regulatory circuits that activate autophagy, and how they enable reprogramming of PDA cell metabolism are unknown. We now show that autophagy regulation in PDA occurs as part of a broader program that coordinates activation of lysosome biogenesis, function and nutrient scavenging, through constitutive activation of the MiT/TFE family of bHLH transcription factors. In PDA cells, the MiT/TFE proteins - MITF, TFE3 and TFEB - override a regulatory mechanism that controls their nuclear translocation, resulting in their constitutive activation. By orchestrating the expression of a coherent network of genes that induce high levels of lysosomal catabolic function, the MiT/TFE factors are required for proliferation and tumorigenicity of PDA cells. Importantly, unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosomal activation is specifically required to maintain intracellular AA pools in PDA. This AA flux is part of a program that is essential for metabolic homeostasis and bioenergetics of PDA but not for their non-transformed counterparts. These results identify the MiT/TFE transcription factors as master regulators of the autophagy-lysosomal system in PDA and demonstrate a central role of the autophagosome-lysosome compartment in maintaining tumor cell metabolism through alternative amino acid acquisition and utilization. Examination of mRNA levels in pancreatic ductal adenocarcinoma (PDA) cell line 8988T after treatment with siRNA for control or TFE3
2015-04-03 | E-GEOD-62077 | biostudies-arrayexpress
Project description:Transcription factro-EB (TFEB) is a master gene for autophagy and lysosome biogenesis We used microarrays to detail the gene expression in TFEB-overexpressing endothelial cells and identified distinct classes of TFEB-regulated genes.
2018-05-01 | GSE108384 | GEO
Project description:Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy with critical roles in several cancers. Lysosomal autophagy promotes cancer survival through degradation of toxic molecules and maintenance of adequate nutrient supply. Doxorubicin (DOX) is the standard of care treatment for triple-negative breast cancer (TNBC); however, chemoresistance at lower doses and toxicity at higher doses limit its usefulness. By targeting pathways of survival, DOX can become an effective antitumor agent. In this study, we examined the role of TFEB in TNBC and its relationship with autophagy and DNA damage induced by DOX. In TNBC cells, TFEB was hypo-phosphorylated and localized to the nucleus upon DOX treatment. TFEB knockdown decreased the viability of TNBC cells while increasing caspase-3 dependent apoptosis. Additionally, inhibition of TFEB-phosphatase calcineurin sensitized cells to DOX-induced apoptosis in a TFEB dependent fashion. Regulation of apoptosis by TFEB was not a consequence of altered lysosomal function, as TFEB continued to protect against apoptosis in the presence of lysosomal inhibitors. RNA-Seq analysis of TFEB knockdown MDA-MB-231 cells identified a significant downregulation in cell cycle and homologous recombination while genes involved in interferon-γ and TNFα signaling were upregulated. In consequence, knockdown of TFEB was found to disrupt DNA repair following DOX, as evidenced by persistent γH2A.X detection. Together, these findings describe in TNBC a novel lysosomal independent function for TFEB in responding to DNA damage.
2020-12-22 | GSE139203 | GEO
Project description:Transcription factro-EB (TFEB) is a master gene for autophagy and lysosome biogenesis We used microarrays to detail the gene expression in TFEB-overexpressing vascular smooth muscle cells identified distinct classes of TFEB-regulated genes.
2020-11-21 | GSE138000 | GEO
Project description:Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages, including autophagy and lipid metabolism. Inflammasome activation and IL1-beta secretion are implicated in atherogenesis, ischemic cardiac injury and resultant heart failure; however, little is known about the role of macrophage lysosome function in regulating these processes. We hypothesized that macrophages exhibit lysosome dysfunction in heart failure due to ischemic injury, and that augmentation of macrophage lysosomal biogenesis via macrophage-specific overexpression of transcription factor EB (mf-TFEB) would attenuate ischemic remodeling by modulating macrophage inflammatory responses. In both mice subject to ischemia-reperfusion injury, and human heart tissue from patients with ischemic cardiomyopathy, we find evidence of lysosome insufficiency and autophagic impairment, respectively. Mf-TFEB overexpression significantly attenuated post-IR adverse left ventricular remodeling at 4 weeks without affecting scar size. Mf-TFEB overexpression reduced the relative amounts of pro-inflammatory macrophage populations in the myocardium. RNA sequencing of flow-sorted cardiac macrophages post-IR confirmed that TFEB stimulated a lysosomal transcriptional program in macrophages, and upregulated key targets involved in lysosomal lipid metabolism, which we show are critical for inflammasome suppression. Both TFEB-dependent inflammasome suppression and effects on post-IR remodeling were independent of autophagy. Our findings suggest that TFEB reprograms macrophage lysosomal lipid metabolism to attenuate inflammasome activity and protect against post-ischemic cardiac remodeling and simultaneously shift our understanding of how autophagy and lipid metabolism impact acute inflammation.
2019-11-01 | GSE118463 | GEO