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Vhl and Rassf1a mutations cause DNA damage, chromosomal instability and induce gene expression changes characteristic of ccRCC [bulk RNA-seq]

ABSTRACT: RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused accumulation of chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity. Combined Rassf1a and Vhl deletion in renal epithelial cells in vivo increased proliferation and caused mild tubular disorganization, but did not lead to the development of kidney tumors. Single cell RNA-sequencing unexpectedly revealed that Rassf1a deletion or Vhl deletion both induce the expression of an overlapping set of genes in a sub-population of proximal tubule cells. Many of these genes are also upregulated in the Vhl/Trp53/Rb1 deficient mouse model of ccRCC. In other subsets of proximal tubule cells, combined Vhl/Rassf1a deletion induced the expression of additional genes that were not upregulated in each of the single knockouts. The expression of the human homologues of Rassf1a-regulated genes correlate negatively with RASSF1 expression levels in human ccRCC, suggesting that the loss of RASSF1A function establishes a ccRCC-characteristic gene expression pattern.

ORGANISM(S): Mus musculus

PROVIDER: GSE280300 | GEO | 2025/02/11

REPOSITORIES: GEO

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Vhl and Rassf1a mutations cause DNA damage, chromosomal instability and induce gene expression changes characteristic of ccRCC [scRNA-seq]

Project description:RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused accumulation of chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity. Combined Rassf1a and Vhl deletion in renal epithelial cells in vivo increased proliferation and caused mild tubular disorganization, but did not lead to the development of kidney tumors. Single cell RNA-sequencing unexpectedly revealed that Rassf1a deletion or Vhl deletion both induce the expression of an overlapping set of genes in a sub-population of proximal tubule cells. Many of these genes are also upregulated in the Vhl/Trp53/Rb1 deficient mouse model of ccRCC. In other subsets of proximal tubule cells, combined Vhl/Rassf1a deletion induced the expression of additional genes that were not upregulated in each of the single knockouts. The expression of the human homologues of Rassf1a-regulated genes correlate negatively with RASSF1 expression levels in human ccRCC, suggesting that the loss of RASSF1A function establishes a ccRCC-characteristic gene expression pattern.

2025-02-11 | GSE280281 | GEO

Genome-wide Screening Identifies SFMBT1 as an Oncogenic Driver in Cancer with VHL Loss

Project description:von Hippel-Lindau (VHL) is a critical tumor suppres- sor in clear cell renal cell carcinomas (ccRCCs). It is important to identify additional therapeutic targets in ccRCC downstream of VHL loss besides hypox- ia-inducible factor 2a (HIF2a). By performing a genome-wide screen, we identified Scm-like with four malignant brain tumor domains 1 (SFMBT1) as a candidate pVHL target. SFMBT1 was considered to be a transcriptional repressor but its role in cancer remains unclear. ccRCC patients with VHL loss-of- function mutations displayed elevated SFMBT1 pro- tein levels. SFMBT1 hydroxylation on Proline residue 651 by EglN1 mediated its ubiquitination and degra- dation governed by pVHL. Depletion of SFMBT1 abolished ccRCC cell proliferation in vitro and in- hibited orthotopic tumor growth in vivo. Integrated analyses of ChIP-seq, RNA-seq, and patient prog- nosis identified sphingosine kinase 1 (SPHK1) as a key SFMBT1 target gene contributing to its onco- genic phenotype. Therefore, the pVHL-SFMBT1- SPHK1 axis serves as a potential therapeutic avenue for ccRCC

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RNAseq transcriptome analysis of THP-1 macrophages activated by VHL-deficient kidney tubule cells

Project description:Clear-cell renal cell carcinoma (ccRCC) is the most prevalent subtype of renal cell carcinoma (up-to 70% of all RCC types). There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL and nearly 100% familial ccRCC (in VHL disease) contain VHL deficiency. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation and this solid tumor contains a substantial number of infiltrated immune cells. This indicates that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory microenvironment. In this study we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to ccRCC formation, and found that human macrophages induced by VHL-deficient kidney tubule cells exhibit distinct gene expression program containing the signatures of tumor-associated macrophages that can promote ccRCC progression.

2022-03-12 | GSE183976 | GEO

Towards a CRISPR-Based Mouse Model of Vhl-deficient Clear Cell Kidney Cancer: Initial Experience and Lessons Learned

Project description:CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1 and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard of care agent, axitinib. RNAseq analysis was utilized to evaluate the expression profile produced by the targeted loss of Vhl, Pbrm1, Keap1 and Tsc1 in these mouse tumors. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2-independent.

2024-08-24 | GSE275231 | GEO

Patterns of gene expression and copy-number alterations in VHL disease-associated and sporadic ccRCC

Project description:Recent insights into the role of the VHL tumor suppressor gene in hereditary and sporadic clear cell carcinoma of the kidney (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of 3 genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors, and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into 2 groups: one group with genomic profiles highly dissimilar to the majority of ccRCC, and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL. Keywords: comparative genomic hybridization 90 clear cell renal cell carcinomas and 21 renal cancer cell lines were subject to 250K SNP analysis.

2010-04-10 | E-GEOD-14994 | biostudies-arrayexpress

The tumor suppressor Rassf1a prevents mouse liver tumorigenesis and regulates levels of the oncogenic kinase Tbk1 and of beta tubulin gene expression in the liver

Project description:The tumor suppressor gene RASSF1A (Ras association domain family protein 1A) coding for a microtubule stabilizing protein is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologues of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic because Hippo pathway components are rarely mutated. Rassf1a homozygous knockout mice developed liver tumors. However, heterozygous deletion of Sav1 or co-deletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A binding partners by mass spectrometry identified the Hippo kinases MST1, MST2 and the oncogenic IkB kinase TBK1 as the most significantly enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a-/- livers was more deregulated than that of Sav1+/- livers and the transcriptome of Rassf1a-/-, Sav1+/- livers was similar to that of Rassf1a-/- mice. We found that the levels of Tbk1 protein were substantially upregulated in livers lacking Rassf1a, and at the transcript level, factors regulating Tbk1 stability, including Usp2 and Dtx4, were also dysregulated. Furthermore, transcripts of several beta tubulin isoforms were increased in the Rassf1a-deficient liver genotypes presumably reflecting a role of Rassf1a as a tubulin-binding and microtubule-stabilizing protein. Our data suggest a multifactorial role of Rassf1a in suppression of liver carcinogenesis.

2016-05-31 | GSE73911 | GEO

The tumor suppressor Rassf1a prevents mouse liver tumorigenesis and regulates levels of the oncogenic kinase Tbk1 and of beta tubulin gene expression in the liver

2016-05-31 | E-GEOD-73911 | biostudies-arrayexpress

Tsc1 and Vhl loss cooperates to drive renal cell carcinoma through augmenting HIF1 and NRF2 signaling pathways

Project description:Besides the truncal VHL mutations, ccRCC is characterized by upregulated MTOR signals from both preclinical and clinical studies. To understand how upregulated MTOR signals cooperate with VHL loss in promoting kidney tumorigenesis, we generated kidney-specific deletion of Vhl and Tsc1 (Vhl;Tsc1 cDKO) in mice. The mice showed decreased life span with maximal age of 11 weeks, bilateral polycystic kidney diseases from ~3 weeks and multifocal solid renal cell carcinoma with eosinophilic cytoplasm and grade 2-3 from 7 weeks old. The mouse tumors resemble histology of the human kidney tumors with VHL and TSC1 mutations. To understand the mechanism of how Tsc1 loss cooperates with Vhl loss in promoting tumorigenesis, we performed transcriptomic, metabolomic and immunohistochemical profilings of renal cortices from age-matched wild-type, Vhl or Tsc1 single knockout, and Vhl;Tsc1 cDKO mice. Tsc1 loss cooperates with Vhl loss by augmenting the HIF1 transcriptional output, as well as altering the glutamine/glutamate metabolism, urea cycle, glycogen metabolism, and activating NRF2 signaling pathways which reprogram the cells to counteract the high oxidative stress associated with the proliferation. Our study reports a ccRCC mouse model recapitulating human ccRCC with same genetic background, provides mechanistic insights concerning cooperation between upregulated mTORC1 signals and VHL loss, generates in vivo reagents for studying ccRCC, and implicates potential clinical values.

2022-05-01 | GSE131735 | GEO

Gene expression data from the 786-O renal cell carcinoma cell line and its metastatic derivatives.

Project description:Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (CYTIP) expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway. Gene expression profiles of 786-O renal cell carcinoma cells and metastatic subpopulations isoloated by in vivo selection in immunocomrpmized mice. The derivatives are significantly enriched in the metastatic propensity as measure by experimental metastasis assays.

2012-12-05 | E-GEOD-32295 | biostudies-arrayexpress

Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease

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

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