Transcriptomic analysis of renal cell carcinoma and cysts in a patient affected by von Hippel Lindau disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254445 | GEO | 2026/02/11
REPOSITORIES: GEO
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Project description:Von Hippel-Lindau (VHL) gene mutations induce neural tissue hemangioblastomas as well as highly vascularized clear cell renal cell carcinomas (ccRCCs). Pathological vessel remodeling arises from mis-regulation of hypoxia inducible factors and vascular endothelial growth factor, among other genes. Variation in disease penetrance has long been recognized in relation to genotype. We show Vhl mutations also disrupt Notch signaling, causing mutation-specific vascular abnormalities e.g. type 1 (null) vs. type 2B (murine G518A representing human R167Q). In conditional mutation retina vasculature, Vhl null mutation (i.e. UBCCreER/+; Vhlfl/fl) had little effect on initial vessel branching, but severely reduced arterial and venous branching at later stages. Interestingly, this mutation accelerated arterial maturation, as observed in retina vessel morphology and aberrant a-smooth muscle actin localization, particularly in vascular pericytes. RNA sequencing analysis identified gene expression changes within several key pathways including Notch and smooth muscle cell contractility. Notch inhibition failed to reverse later-stage branching defects but rescued the accelerated arterialization. Retinal vessels harboring the type 2B Vhl mutation (i.e. UBCCreER/+; Vhlfl/2B) displayed stage-specific changes in vessel branching and an advanced progression toward an arterial phenotype. Disrupting Notch signaling in 2B mutants increased both artery and vein branching, and restored arterial maturation toward non-mutant levels. By revealing differential effects of the null and type 2B Vhl mutations on vessel branching and maturation, these data may provide insight into the variability of VHL-associated vascular changes, particularly the heterogeneity and aggressiveness in ccRCC vessel growth, as well as suggest Notch pathway targets for treating VHL syndrome.
2019-08-20 | GSE109102 | GEO
Project description:Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome caused by germline pathogenic variants in the VHL gene. Affected individuals develop multiple primary tumours in several organs, but the determinant of their life expectancy is clear cell renal cell carcinoma (ccRCC). The current standard of care is based on arbitrary decisions. Due to the lack of biological or molecular markers assisting clinical decision-making, patients undergo multiple surgical interventions with an incremental risk of complications and morbidity. The most important clinical need in those individuals is to overcome intra/intertumoral heterogeneity in VHL-associated ccRCC to allow tailored decisions and treatments. Therefore, we set up a methodology aiming at creating the first integrated map of intra- and inter-tumour heterogeneity in VHL-associated ccRCC by overlaying imaging, histology, multiplex immunohistochemistry, and multi-omics data from multi-region tumour biopsies. This, combined with the establishment of patient derived organoids cultures, can provide innovative tools to guide clinical management.
2025-12-04 | GSE288008 | GEO
Project description:Von Hippel-Lindau (VHL) dìsease is a rare inherited disorder caused by the loss of the VHL gene and characterized by benign and malignant tumors in several organs. Patients with VHL disease have risk of developing multiple primary clear cell renal carcinomas (ccRCC). Patients are managed with multiple sessions of renal surgery causing renal failure and complication of dialysis or systemic progression and cancer-specific mortality. Our hypothesis states that multiple independent tumors from one VHL patient may display inter-tumoral heterogeneity characterized by differences in tumor grade, metabolic, stromal, and immune cell features that may cause different response to systemic therapy. We took advantage of a nephrectomy from one VHL patient to investigate molecular and microenvironmental factors in five independent primary tumors.
2026-02-11 | GSE254444 | GEO
Project description:We report transcriptome analysis (RNAseq) of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are in disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, as well as an immune response and oxidative metabolic gene downregulation, that induces oxidative stress. These results would suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in VHL gene.
2021-08-04 | GSE181417 | GEO
Project description:We have generated two zebrafish lines carrying inactivating germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene ortholog vhl. Mutant embryos display a general systemic hypoxic response, including the upregulation of hypoxia-induced genes by 1 day post-fertilization and a severe hyperventilation and cardiophysiological response. vhl mutants develop polycythemia with concomitantly increased epo/epor mRNA levels and Epo signaling. In situ hybridizations reveal global up-regulation of both red and white hematopoietic lineages. Hematopoietic tissues are highly proliferative, with enlarged populations of c-myb+ HSCs and circulating erythroid precursors. Chemical activation of Hif-signaling recapitulated aspects of the vhl-/- phenotype. Furthermore, microarray expression analysis confirms the hypoxic response and hematopoietic phenotype observed in vhl-/- embryos. We conclude that Vhl participates in regulating hematopoiesis and erythroid differentiation. Injections with human VHLp30 and R200W mutant mRNA demonstrate functional conservation of VHL between mammals and zebrafish at the amino acid level, indicating that vhl mutants are a powerful new tool to study genotype-phenotype correlations in human disease. Zebrafish mutants are the first congenital embryonic viable systemic vertebrate animal model for VHL, representing the most accurate model for VHL-associated polycythemia to date. They will contribute to our understanding of hypoxic signaling, hematopoiesis and VHL-associated disease progression.
2009-03-01 | GSE14866 | GEO
Project description:To establish the role of proximal tubular hypoxia in diabetic kidney disease, we use a mouse line with a specific deletion of von-Hippel-Lindau (VHL) in the proximal tubule and treat them with streptozotocin (STZ) to induce a type I diabetes mellitus. 10 weeks after induction of diabetes mellitus samples were collected.
2022-08-08 | GSE210401 | GEO
Project description:N6‐Methyladenosine (m6A) is the most abundant internal post‐translational modification, and its contribution to cancer evolution has recently been appreciated. Renal cancer is the most common adult genitourinary cancer, of which ~85% is accounted for by the clear cell subtype (ccRCC) characterized by VHL loss. In this study, we demonstrate for the first time that VHL binds with m6A enzymatic complex proteins and promotes METTL3-METTL14 complex formation, and VHL depletion suppresses mRNA m6A modification. m6A RIP-seq coupled with RNA-seq in renal cells with or without VHL allowed us to identify a selection of genes whose expression may be regulated by m6A. Specifically, PIK3R3 is identified to be one critical gene whose mRNA stability is regulated by VHL in a m6A-dependent but HIF-independent manner. Functionally, PIK3R3 depletion promotes renal cancer cell growth and orthotopic tumor growth while vice versa. Mechanistically, PIK3R3 suppresses tumor growth by restraining PI3K/AKT activity. Taken together, we propose a new mechanism by which VHL regulates m6A through modulation of METTL3-METTL14 protein complex formation, thereby promoting PIK3R3 mRNA stability and protein level that is critical for regulating ccRCC tumorigenesis.
2024-03-19 | GSE239892 | GEO
Project description:We and others have previously shown that glomerular endothelial cells and podocytes express hypoxia-inducible transcription factors (HIFs). HIFs bind to hypoxia response elements in target genes, such as vascular endothelial growth factor, which is continually produced by podocytes throughout life. To further assess function of HIFs in podocyte biology, podocin-Cre mice were mated with floxed von Hippel-Lindau (VHL) mice to selectively delete VHL, a component of an E3 ligase complex responsible for degradation of HIFs in normoxia. We reasoned that cells lacking VHL would overexpress stable HIFs and upregulate hypoxia-responsive genes. Progeny from these crosses displayed two phenotypes, non-proteinuric with glomerular basement membrane (GBM) defects and proteinuric with GBM defects and end-stage renal failure at ~6 months of age. Gene changes associated with the mild, non-proteinuric phenotype were studied using isolated glomeruli from wildtype and Pod-Cre fVHL mice.
2010-08-03 | GSE20235 | GEO
Project description:We and others have previously shown that glomerular endothelial cells and podocytes express hypoxia-inducible transcription factors (HIFs). HIFs bind to hypoxia response elements in target genes, such as vascular endothelial growth factor, which is continually produced by podocytes throughout life. To further assess function of HIFs in podocyte biology, podocin-Cre mice were mated with floxed von Hippel-Lindau (VHL) mice to selectively delete VHL, a component of an E3 ligase complex responsible for degradation of HIFs in normoxia. We reasoned that cells lacking VHL would overexpress stable HIFs and upregulate hypoxia-responsive genes. Progeny from these crosses displayed two phenotypes, non-proteinuric with glomerular basement membrane (GBM) defects and proteinuric with GBM defects and end-stage renal failure at ~6 months of age. Gene changes associated with the mild, non-proteinuric phenotype were studied using isolated glomeruli from wildtype and Pod-Cre fVHL mice. At 4 weeks of age, urine was collected and urinary albumin was quantified by Albuwell elisa from Pod-Cre fVHL litters. At 6 weeks of age, glomeruli from 3 wildtype littermate controls and 3 non-proteinuric Pod-Cre fVHL mice were collected using the magnetic bead method. RNA was extracted and hybridized to Affymetrix microarrays.
2010-08-03 | E-GEOD-20235 | biostudies-arrayexpress
Project description:The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated a subunits of hypoxia-inducible factor (HIF). Although studies of VHL defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF dependent and independent effects of VHL inactivation by studying gene expression patterns in C. elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1 independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17 and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1 independent function of VHL-1 that is connected with extracellular matrix function. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Bishop T, Lau KW, Epstein AC, Kim SK, Jiang M, O'rourke D, Pugh CW, Gleadle JM, Taylor MS, Hodgkin J, Ratcliffe PJ, Genetic Analysis of Pathways Regulated by the von Hippel-Lindau Tumor Suppressor in Caenorhabditis elegans., Bishop T, et al. (2004) PLoS Biol 2(10):e289, 2004-10-01, http://biology.plosjournals.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020289 Computed
2005-07-20 | E-GEOD-2963 | biostudies-arrayexpress