Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ...ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1α pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors.
Display omitted
•Elevated intracellular fumarate indirectly activates ABL1•ABL1 promotes HIF-dependent aerobic glycolysis in FH-deficient tumor cells•ABL1 stimulates the NRF2-dependent antioxidant response pathway•ABL1 inhibition provides a strategy to treat oxidatively stressed tumors
Sourbier et al. report ABL1 activation in fumarate hydratase (FH)-deficient kidney tumors, promoting aerobic glycolysis and NRF2-mediated antioxidant defense. ABL1 inhibition may be clinically useful for the treatment of FH-deficient kidney cancer and other glycolytic, oxidatively stressed tumors.
To characterize the clinical presentation, genomic alterations, pathologic phenotype and clinical management of microphthalmia-associated transcription factor (MITF) familial renal cell carcinoma ...(RCC), caused by a member of the TFE3, TFEB, and MITF family of transcription factor genes.
The clinical presentation, family history, tumor histopathology, and surgical management were evaluated and reported herein. DNA sequencing was performed on blood DNA, tumor DNA and DNA extracted from adjacent normal kidney tissue. Copy number and gene expression analyses on tumor and normal tissues were performed by Real-Time Polymerase chain reaction. TCGA gene expression data were used for comparative analysis. Protein expression and subcellular localization were evaluated by immunohistochemistry.
Germline genomic analysis identified the MITF p.E318K variant in a patient with bilateral, multifocal type 1 papillary RCC and a family history of RCC. All tumors displayed the MITF variant and were characterized by amplification of chromosomes 7 and 17, hallmarks of type 1 papillary RCC. We demonstrated that MITF p.E318K variant results in altered transcriptional activity and that downstream targets of MiT family members, such as GPNMB, are dysregulated in the tumors.
Association of the pathogenic MITF variant with bilateral and multifocal type 1 papillary RCC in this family supports its role as a risk allele for the development of RCC and emphasizes the importance of screening for MITF variants irrelevant of the RCC histologic subtype. This study identifies potential biomarkers for the disease, such as GPNMB expression, that may facilitate the development of targeted therapies for patients affected with MITF-associated RCC.
This report describes a case study of a patient with bilateral, multifocal type 1 papillary renal cell carcinoma (RCC) and a family history of RCC that has the germline MITF p.E318K variant, known to predispose to kidney cancer. All tumors demonstrated a papillary type 1 histology and analyses of available tumors identified increased nuclear staining for the MITF transcription factor, somatic amplification of chromosomes 7 and 17, and altered expression of genes associated with tumorigenesis, including potential biomarkers, such as GPNMB. Display omitted
Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) are associated with an increased risk of aggressive and early ...metastasizing variants of renal cell carcinoma (RCC). These RCCs express significantly increased levels of intracellular fumarate or succinate that inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. This study evaluated the genome-wide methylation profiles of 34 RCCs from patients with RCC susceptibility syndromes and 11 associated normal samples using the Illumina HumanMethylation450 BeadChip. All the HLRCC (FH mutated) and SDHB-RCC (SDHB mutated) tumors demonstrated a distinct CpG island methylator phenotype (CIMP). HLRCC tumors demonstrated an extensive and relatively uniform level of hypermethylation that showed some correlation with tumor size. SDHB-RCC demonstrated a lesser and more varied pattern of hypermethylation that overlapped in part with the HLRCC hypermethylation. Combined methylation and mRNA expression analysis of the HLRCC tumors demonstrated hypermethylation and transcription downregulation of genes associated with the HIF pathway, HIF3A and CITED4, the WNT pathway, SFRP1, and epithelial-to-mesenchymal transition and MYC expression, OVOL1. These observations were confirmed in the TCGA CIMP-RCC tumors. A selected panel of probes could identify the CIMP tumors and differentiate between HLRCC and SDHB-RCC tumors. This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Published series of growth rates of renal tumors on active surveillance largely consist of tumors without pathologic or genetic data. Growth kinetics of genetically defined renal tumors are not well ...known. Here, we evaluate the growth of genetically defined renal tumors and their association with patient clinical and genetic characteristics.
We evaluated patients with an inherited kidney cancer susceptibility syndrome as a result of a pathologic germline alteration of
or
with at least 1 solid renal mass managed with active surveillance at our institution. Tumor growth rates (GR) were calculated and patients were stratified by genetic alteration and other clinical and genetic factors to analyze differences in growth rates using linear regression and comparative statistics.
A total of 292 patients with 435 genetically defined tumors were identified, including 286
-deficient, 91
-deficient, 52
-activated, and 6
-deficient tumors. There were significant differences in GRs when stratified by genetic alteration.
-deficient tumors had the fastest median GR (0.6 cm/y; interquartile range IQR, 0.57-0.68 cm/y), followed by
-deficient tumors (GR, 0.37 cm/y; IQR, 0.25-0.57 cm/y),
-deficient tumors (GR, 0.10 cm/y; IQR, 0.04-0.24 cm/y), and tumors with
activation (GR, 0.15 cm/y; IQR, 0.053-0.32 cm/y;
< .001). Tumors from the same patient had similar GRs. Younger age was independently associated with higher GR (
= .005).
In a cohort of genetically defined tumors, tumor growth rates varied in a clinically and statistically different manner according to genetic subtype. Rapid growth of
-deficient tumors indicates that these patients should be managed with caution. The faster growth of tumors in younger patients may support more frequent imaging, whereas the slower growth of other tumors may support extended surveillance beyond annual imaging in some instances.
Purpose Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits ( SDHB / C / D ) of the Krebs cycle enzyme, succinate dehydrogenase. We report our ...experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. Materials and Methods Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB , SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. Results A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. Conclusions SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors.
Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown ...unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of
and
genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.
Birt‐Hogg‐Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss‐of‐function ...pathogenic variants in the gene encoding the tumor‐suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney‐specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient‐derived tumor samples revealed increased activation of TFEB/TFE3‐mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line‐derived xenografts (CDXs). Our findings demonstrate in disease‐relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.
Synopsis
TFEB and TFE3 transcription factors are master regulators of cell metabolism. This study shows that in Birt‐Hogg‐Dubé (BHD) hereditary cancer syndrome, these factors concomitantly activate cellular catabolic and anabolic pathways, playing a key role in kidney cystogenesis and tumorigenesis.
Genetic interaction studies revealed that TFEB and TFE3 have a differential and cooperative role in the kidney phenotype of a mouse model of BHD syndrome.
Transcriptomic and proteomic analyses of tumor samples from BHD patients showed upregulation of the TFEB/TFE3 transcriptional program and induction of both lysosomal and mTORC1 pathways.
Depletion of TFEB or TFE3 fully abrogated the growth of BHD renal tumor cells in xenograft experiments, indicating that both genes are key drivers of tumorigenesis.
TFEB and TFE3 transcription factors are master regulators of cell metabolism. This study shows that in Birt‐Hogg‐Dubé (BHD) hereditary cancer syndrome, these factors concomitantly activate cellular catabolic and anabolic pathways, playing a key role in kidney cystogenesis and tumorigenesis.
Oncocytomas are mostly benign tumors characterized by accumulation of defective mitochondria, and in sporadic cases, are associated with disruptive mitochondrial DNA (mtDNA) mutations. However, the ...role mtDNA mutations have in renal tumors of Birt-Hogg-Dubé (BHD) patients and other renal oncocytomas with an apparent genetic component has not been investigated to date. Here we characterize the mitochondrial genome in different renal tumors and investigate the possibility of employing mtDNA sequencing analyses of biopsy specimens to aid in the differential diagnosis of oncocytomas. The entire mitochondrial genome was sequenced in 25 samples of bilateral and multifocal (BMF) renal oncocytomas, 30 renal tumors from BHD patients and 36 non-oncocytic renal tumors of different histologies as well as in biopsy samples of kidney tumors. mtDNA sequencing in BMF oncocytomas revealed that all tumors carry disruptive mutations, which impair the assembly of the NADH-ubiquinone oxidoreductase. Multiple tumors from a given BMF oncocytoma patient mainly harbor the same somatic mutation and the kidneys of these patients display diffuse oncocytosis. In contrast, renal oncocytomas of patients with BHD syndrome and renal tumors with different histologies do not show disruptive mtDNA mutations. Moreover, we demonstrate that it is feasible to amplify and sequence the entire mtDNA in biopsy specimens, and that these sequences are representative of the tumor DNA. These results show that pathogenic mtDNA mutations affecting complex I of the respiratory chain are strongly correlated with the oncocytoma phenotype in non-BHD-related renal tumors and that mtDNA sequences from biopsies are predictive of the tumor genotype. This work supports a role for mtDNA mutations in respiratory chain complexes as diagnostic markers for renal oncocytomas.
Mutations in the Fe-S cluster-containing SDHB subunit of succinate dehydrogenase cause familial cancer syndromes. Recently the tripeptide motif L(I)YR was identified in the Fe-S recipient protein ...SDHB, to which the cochaperone HSC20 binds.
In order to characterize the metabolic basis of SDH-deficient cancers we performed stable isotope-resolved metabolomics in a novel SDHB-deficient renal cell carcinoma cell line and conducted bioinformatics and biochemical screening to analyze Fe-S cluster acquisition and assembly of SDH in the presence of other cancer-causing SDHB mutations.
We found that the SDHBR46Q mutation in UOK269 cells disrupted binding of HSC20, causing rapid degradation of SDHB. In the absence of SDHB, respiration was undetectable in UOK269 cells, succinate was elevated to 351.4 ± 63.2 nmol/mg cellular protein, and glutamine became the main source of TCA cycle metabolites through reductive carboxylation.Furthermore, HIF1α, but not HIF2α, increased markedly and the cells showed a strong DNA CpG island methylatorphenotype (CIMP). Biochemical and bioinformatic screening revealed that 37% of disease-causing missense mutations in SDHB were located in either the L(I)YR Fe-S transfer motifs or in the 11 Fe-S cluster-ligating cysteines.
These findings provide a conceptual framework for understanding how particular mutations disproportionately cause the loss of SDH activity, resulting in accumulation of succinate and metabolic remodeling in SDHB cancer syndromes.
PDF
