Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-Ribose Polymerase inhibitors and low-dose alkylating chemotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201008 | GEO | 2022/04/21
REPOSITORIES: GEO
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Project description:Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we evaluated novel treatment approaches in newly generated models of FH- and SDHB-deficient RCC.
2022-05-28 | GSE204846 | GEO
Project description:Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) have been associated with an increased risk of renal cell carcinoma (RCC). These RCCs are characterized by loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. These tumors represent aggressive forms of RCC that can metastasize early and require specific patient management and treatment. Therefore, identifying effective and accurate methods for diagnosing these tumors is very beneficial. This study evaluated and compared the genome-wide methylation profiles of 33 RCCs from patients with RCC susceptibility syndromes, 10 associated normal samples and 13 cell-line models using the Illumina HumanMethylation450 BeadChip assay. Fifteen tumors derived from patients with germline FH (n=9) or SDHB (n=6) mutations demonstrated a distinct pattern of hypermethylation (R-CIMP) with enrichment for hypermethylation within the CpG island regions. A small, selected panel of probes was characterized that could identify R-CIMP and distinguish between FH and SDHB tumors. Cell-line models derived from HLRCC (n=3) or SDHB (n=1) kidney tumors demonstrated similar patterns of hypermethylation to the tumors, yet re-expression of either wild-type FH or SDHB did not alter the hypermethylation pattern. Treatment of the cell line models with 5-aza-2′-deoxycytidine resulted in reduced rates of invasion.
2020-10-31 | GSE126441 | GEO
Project description:Fumarate Hydratase (FH) is a mitochondrial enzyme that catalyses the reversible hydration of fumarate to malate in the TCA cycle. Germline mutations of FH lead to HLRCC, a cancer syndrome characterised by a highly aggressive form of renal cancer(1). Although HLRCC tumours metastasise rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas(2). How Fh1-deficient cells overcome these tumour suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR/Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the HIRA enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss enables the activation of MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
2022-10-29 | GSE203056 | GEO
Project description:Conducting an in-depth exploration of the multi-omics landscape of Fumarate Hydratase (FH)-deficient renal cell carcinoma (RCC), the study aimed to unravel the intricate molecular mechanisms underlying this rare and aggressive form of renal cancer. Analyzing 126 patients with FH-deficient RCC, we identified distinct variant spectrum of FH gene, with truncating mutation correlated with adverse prognostic factors and a worse response to immune checkpoint blockade. The identification of three molecular subtypes with diverse clinical/genomic characteristics and varying response to systemic treatment further enriched the understanding of the heterogeneous tumor microenvironment (particularly immune-related) in FH-deficient RCC, and suggested potential therapeutic targets. These findings offer a basis for molecular stratification, shedding light on the tailored therapeutic strategies in improving treatment response of FH-deficient RCC.
2024-10-20 | GSE273036 | GEO
Project description:<p>Germline or somatic loss-of-function of fumarate hydratase (FH) predisposes patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection, there is no effective therapy for FH-deficient RCC, a competent method for early diagnosis and for early detection of recurrent and metastatic disease is an unmet clinical need. Currently, at best, an annual MRI scan is offered, though typically, MRI is used for symptomatic patients only. Therefore, finding specific and sensitive biomarkers suitable for routine and simple screens is crucial for improving the clinical outcome of these patients. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed a large-scale study of plasma metabolomics comparing FH-deficient RCC patients to no-tumor control individuals or to wildtype FH RCC patients. Our results indicated two fumarate-derived metabolites, succinyl-adenosine and succinic-cysteine, to be outstanding plasma biomarkers for early diagnosis, with a positive predictive value of more than 90%. Furthermore, using pre-clinical and biochemical studies, we identified the enzymatic mechanisms by which these biomarkers are produced in and around the tumors. </p>
2022-08-12 | MTBLS3628 | MetaboLights
Project description:Purpose: Identifying transcriptional changes led by Hira loss in FH deficient cells Methods: RNA was extracted from the cell lines using QIAGEN kit folloging the manufacturer instructions. RNA concentrator kit was used to guarantee RNA quality. Results/Conclusion: We identified MYC/E2F1 signatures as the top upregulated ones controlling the oncogenic events occuring in Fh1 and Hira deficient cells.
2022-10-29 | GSE201992 | GEO
Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice.
2011-10-24 | GSE29988 | GEO
Project description:Fumarate hydratase (FH) mutations predispose to renal cysts cancer. These cancers overexpress hypoxia-inducible factor-alpha (Hif-1a). We have generated a conditional Fh1 (mouse FH) knockout mice that develop renal cysts and overexpress Hif-1a. In order to identify the contribution of Hif-1a to cyst formation we have intercrossed our mice with conditional HIf-1a KO mice. We intercrossed Fh1/Hif1a mice with kidney specific cre recombinase (Ksp-Cre) and analysed kidney cyst formation. RNA was extracted from cysts from 4xFh1 KO, 4xFh1/Hif-1a KO and 4 control mice. For each comparison littermates were used and the animals were aged 15 weeks i.e. early cystic disease.
2011-10-23 | E-GEOD-29988 | biostudies-arrayexpress
Project description:Fumarate Hydratase (FH) is an enzyme of the Tricarboxilic Acid Cycle (TCA) that catalyzes the conversion of fumarate into malate. In the last decade, studies have revealed FH as a bona fide tumour suppressor whose mutations cause Hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Loss of FH in the kidney elicits several oncogenic signalling cascades through the accumulation of the oncometabolite fumarate. Yet, whilst the long-term consequences of FH loss have been extensively described, the acute response to FH loss has not been investigated due, in part, to the lack of a suitable model. Here, we generated a new inducible mouse model to investigate the chronology of the murine homologue of FH, Fh1, loss in the adult kidney.
2023-02-17 | GSE183745 | GEO
Project description:Fumarate hydratase (FH) mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC). We have conditionally inactivated the murine ortholog (Fh1) in renal tubular epithelial cells in order to generate an in vivo model of HLRCC. Fh1 knockout mice recapitulates important aspects of HLRCC including the development of renal cysts that overexpress hypoxia inducible factor alpha (Hifa) and Hif-target genes. We used microarrays to detail the global programme of gene expression underlying cyst development in Fh1 knockout mice and identified distinct classes of up-regulated genes during this process. Keywords: gene expression, comparison (wild-type n=3 vs knockout n=3)
2010-12-22 | GSE10989 | GEO