Sriram Venneti

University of Michigan, Ann Arbor, Michigan, United States

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Publications (56)344.11 Total impact

  • Sriram Venneti · Paul S. Mischel

    No preview · Article · Nov 2015 · Brain Pathology
  • Daniel R. Wahl · Sriram Venneti
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    ABSTRACT: Common pathways and mechanisms can be found in both cancers and inborn errors of metabolism. 2-Hydroxyglutarate (2-HG) acidurias and isocitrate dehydrogenase (IDH) 1/2 mutant tumors are examples of this phenomenon. 2-HG can exist in two chiral forms, D(R)-2-HG and L(S)-2-HG, which are elevated in D- and L-acidurias, respectively. D-2-HG was subsequently discovered to be synthesized in IDH 1/2 mutant tumors including ∼70% of intermediate-grade gliomas and secondary glioblastomas (GBM). Recent studies have revealed that L-2-HG is generated in hypoxia in IDH wild-type tumors. Both 2-HG enantiomers have similar structures as α-ketoglutarate (α-KG) and can competitively inhibit α-KG-dependent enzymes. This inhibition modulates numerous cellular processes, including histone and DNA methylation, and can ultimately impact oncogenesis. D-2-HG can be detected in vivo in glioma patients and animal models using advanced imaging modalities. Finally, pharmacologic inhibitors of mutant IDH 1/2 attenuate the production of D-2-HG and show great promise as therapeutic agents.
    No preview · Article · Nov 2015 · Brain Pathology

  • No preview · Article · Nov 2015 · Neuro-Oncology
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    ABSTRACT: Differentiating tumor from normal brain is a major barrier to achieving optimal outcome in brain tumor surgery. New imaging techniques for visualizing tumor margins during surgery are needed to improve surgical results. We recently demonstrated the ability of stimulated Raman scattering (SRS) microscopy, a nondestructive, label-free optical method, to reveal glioma infiltration in animal models. We show that SRS reveals human brain tumor infiltration in fresh, unprocessed surgical specimens from 22 neurosurgical patients. SRS detects tumor infiltration in near-perfect agreement with standard hematoxylin and eosin light microscopy (kappa = 0.86). The unique chemical contrast specific to SRS microscopy enables tumor detection by revealing quantifiable alterations in tissue cellularity, axonal density, and protein/lipid ratio in tumor-infiltrated tissues. To ensure that SRS microscopic data can be easily used in brain tumor surgery, without the need for expert interpretation, we created a classifier based on cellularity, axonal density, and protein/lipid ratio in SRS images capable of detecting tumor infiltration with 97.5% sensitivity and 98.5% specificity. Quantitative SRS microscopy detects the spread of tumor cells, even in brain tissue surrounding a tumor that appears grossly normal. By accurately revealing tumor infiltration, quantitative SRS microscopy holds potential for improving the accuracy of brain tumor surgery.
    No preview · Article · Oct 2015 · Science translational medicine

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the "oncometabolite" D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3). Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Cell metabolism
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    ABSTRACT: Receptor tyrosine kinase (RTK) signaling promotes the growth and progression of glioblastoma (GBM), a highly aggressive type of brain tumor. We previously reported that decreased miR-218 expression in GBM directly promotes RTK activity by increasing the expression of key RTKs and their signaling mediators, including the RTK epidermal growth factor receptor (EGFR), phospholipase C-γ1 (PLCγ1), and the kinases PIK3CA and ARAF. However, increased RTK signaling usually activates negative feedback mechanisms to maintain homeostasis. We found that decreased miR-218 expression in GBM cells also increased the expression of genes encoding additional upstream and downstream components of RTK signaling pathways, including the RTK platelet-derived growth factor receptor α (PDGFRα) and the kinases ribosomal S6 kinase 2 (RSK2) and S6 kinase 1 (S6K1), that collectively overrode the negative feedback mechanism. Furthermore, increased RTK signaling itself suppressed miR-218 expression. Mass spectrometry and DNA pull-down identified binding of signal transducer and activator of transcription 3 (STAT3) along with the transcriptional repressor BCL2-associated transcription factor 1 (BCLAF1) directly to the miR-218 locus. These data identify previously unknown feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · May 2015 · Science Signaling

  • No preview · Article · Apr 2015 · Neuro-Oncology
  • Sriram Venneti · Jason T Huse
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    ABSTRACT: Low-grade gliomas (LGG) constitute grades I and II tumors of astrocytic and grade II tumors of oligodendroglial lineage. Although these tumors are typically slow growing, they may be associated with significant morbidity and mortality because of recurrence and malignant progression, even in the setting of optimal resection. LGG in pediatric and adult age groups are currently classified by morphologic criteria. Recent years have heralded a molecular revolution in understanding brain tumors, including LGG. Next-generation sequencing has definitively demonstrated that pediatric and adult LGG fundamentally differ in their underlying molecular characteristics, despite being histologically similar. Pediatric LGG show alterations in FGFR1 and BRAF in pilocytic astrocytomas and FGFR1 alterations in diffuse astrocytomas, each converging on the mitogen-activated protein kinase signaling pathway. Adult LGG are characterized by IDH1/2 mutations and ATRX mutations in astrocytic tumors and IDH1/2 mutations and 1p/19q codeletions in oligodendroglial tumors. TERT promoter mutations are also noted in LGG and are mainly associated with oligodendrogliomas. These findings have considerably refined approaches to classifying these tumors. Moreover, many of the molecular alterations identified in LGG directly impact on prognosis, tumor biology, and the development of novel therapies.
    No preview · Article · Mar 2015 · Advances in Anatomic Pathology
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    ABSTRACT: Glucose and glutamine are the two principal nutrients that cancer cells use to proliferate and survive. Many cancers show altered glucose metabolism, which constitutes the basis for in vivo positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG). However, (18)F-FDG is ineffective in evaluating gliomas because of high background uptake in the brain. Glutamine metabolism is also altered in many cancers, and we demonstrate that PET imaging in vivo with the glutamine analog 4-(18)F-(2S,4R)-fluoroglutamine ((18)F-FGln) shows high uptake in gliomas but low background brain uptake, facilitating clear tumor delineation. Chemo/radiation therapy reduced (18)F-FGln tumor avidity, corresponding with decreased tumor burden. (18)F-FGln uptake was not observed in animals with a permeable blood-brain barrier or neuroinflammation. We translated these findings to human subjects, where (18)F-FGln showed high tumor/background ratios with minimal uptake in the surrounding brain in human glioma patients with progressive disease. These data suggest that (18)F-FGln is avidly taken up by gliomas, can be used to assess metabolic nutrient uptake in gliomas in vivo, and may serve as a valuable tool in the clinical management of gliomas. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · Feb 2015 · Science translational medicine

  • No preview · Article · Jan 2015 · Cancer Research
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    ABSTRACT: Choroid plexus tumors (CPTs) are rare neoplasms arising from the choroid plexus epithelium, and occur predominantly in infants and children. CPTs may be associated with TP53 germline mutations (Li–Fraumeni syndrome), but the majority of CPTs are sporadic. Most commonly, CPTs present with signs of increased intracranial pressure; on imaging they are characterized as intraventricular contrast-enhancing masses. Histopathologically, CPTs comprise benign choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (APP, WHO grade II), and malignant choroid plexus carcinoma (CPC, WHO grade III). Complete surgical resection may be curative for CPPs, while CPCs are additionally treated with chemotherapy and radiation. In this chapter we discuss these features in detail, as well as differential diagnosis and immunohistochemical studies. Particular emphasis is placed on the molecular alterations, how they can be detected in the laboratory using immunohistochemistry and molecular testing, and how they may lead to novel-targeted therapeutic approaches.
    No preview · Chapter · Jan 2015
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    ABSTRACT: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive and lethal tumors encountered primarily in the pediatric age group. These tumors are defined by mutations and deletions in the SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) gene (also referred to as SNF5/BAF47/INI1) or, in very rare cases, other genes related to the SWI/SNF chromatin remodeling complex. Histologically, these tumors are variable in their appearance and show a spectrum of features, including characteristic rhabdoid cells and immunohistochemical evidence of polyphenotypic differentiation. We discuss the clinical manifestations including epidemiology, neuroradiologic features, histopathology, differential diagnosis, and immunohistochemical studies that aid in the diagnosis of AT/RT. Emphasis is placed on the molecular genetic alterations encountered in this tumor, how detection of genetic alterations in SMARCB1 can be accomplished in the clinical laboratory using immunohistochemistry and molecular approaches, and how these alterations contribute to the elucidation of the pathogenesis of AT/RT. Finally, we outline the poor clinical prognosis borne by patients with AT/RT and discuss the current and potential new treatment regimens that could be used to treat these deadly tumors.
    No preview · Chapter · Jan 2015
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    ABSTRACT: Glutamine is the most abundant plasma amino acid and many cancers show altered glutamine metabolism. We evaluated glutamine uptake and metabolism in gliomas using PET imaging and biochemical approaches. We demonstrate that glutamine is a key TCA cycle anaplerotic substrate and is metabolized to generate 2-HG in IDH1-mutant gliomas. PET imaging with18F-labeled glutamine (18F-FGln) showed high uptake in gliomas in vivo but low background uptake in the surrounding brain in RCAS-PDGF/PTEN null and IDH1-mutant glioma animal models, facilitating clear tumor delineation in contrast to that seen with 18F-FDG. We did not observe 18F-FGln uptake in animals with neuroinflammation or animals with a disrupted BBB. Further, 18F-FGln uptake was specifically reduced on chemo/radiation therapy. Finally, 18F-FGln showed high avidity in human glioma with low uptake in the surrounding brain. These data suggest that 18F-FGln is specifically taken up by gliomas, can be used to assess the metabolic state of gliomas in vivo and may serve as a valuable tool in the clinical management of gliomas.
    Full-text · Article · Nov 2014 · Neuro-Oncology
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    ABSTRACT: Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.
    Full-text · Article · Sep 2014 · Molecular Cell
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    ABSTRACT: Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1338-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Sep 2014 · Acta Neuropathologica
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    ABSTRACT: Unlabelled: The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival. Significance: In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth.
    No preview · Article · Sep 2014 · Cancer Discovery
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    ABSTRACT: Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt's effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.
    Full-text · Article · Jul 2014 · Cell Metabolism
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    ABSTRACT: BACKGROUND: Up to 30% of pediatric glioblastomas (GB) demonstrate mutations in H3F3A, a gene variant encoding histone H3.3. Global reduction in H3K27me3 is associated with H3F3A K27M mutation. METHODS: We evaluated the utility of histopathological detection of this reduction in H3K27me3 as a prognostic biomarker. H3K27me3 expression was established by immunohistochemistry in 160 (118 pediatric and 42 adult) brain tumors of various subtypes and grades and 45 non-neoplastic reactive brain tissues. RESULTS: Global reduction in H3K27me3 was specific to GB cases with the H3F3A K27M mutantion, and was not observed in all other cases examined. In addition, H3F3A K27M mutant GB with reduced H3K27me3 exhibited a poor prognosis compared to H3F3A wild type tumors with preserved H3K27me3 (Log-rank (Mantel-Cox) test hazards ratio = 2.9, p = 0.0021). CONCLUSIONS: Global reduction in H3K27me3 is a histopathologically detectable surrogate for H3F3A K27M mutant GB that defines a poor prognosis subset of pediatric GB. SECONDARY CATEGORY: Pediatrics.
    Preview · Article · Jul 2014 · Neuro-Oncology
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    ABSTRACT: Glioblastomas are aggressive adult brain tumors, characterized by inadequately organized vasculature and consequent nutrient and oxygen (O2)-depleted areas. Adaptation to low nutrients and hypoxia supports glioblastoma cell survival, progression and therapeutic resistance. However, specific mechanisms promoting cellular survival under nutrient and O2 deprivation remain incompletely understood. Here, we show that miR-124 expression is negatively correlated with a hypoxic gene signature in glioblastoma patient samples, suggesting that low miR-124 levels contribute to pro-survival adaptive pathways in this disease. As miR-124 expression is repressed in various cancer types (including glioblastoma), we quantified miR-124 abundance in normoxic and hypoxic regions in glioblastoma patient tissue, and investigated whether ectopic miR-124 expression compromises cell survival during tumor ischemia. Our results indicate that miR-124 levels are further diminished in hypoxic/ischemic regions within individual glioblastoma patient samples, compared with regions replete in O2 and nutrients. Importantly, we also show that increased miR-124 expression affects the ability of tumor cells to survive under O2 and/or nutrient deprivation. Moreover, miR-124 re-expression increases cell death in vivo and enhances the survival of mice bearing intracranial xenograft tumors. miR-124 exerts this phenotype in part by directly regulating TEAD1, MAPK14/p38α and SERP1, factors involved in cell proliferation and survival under stress. Simultaneous suppression of these miR-124 targets results in similar levels of cell death as caused by miR-124 restoration. Importantly, we further demonstrate that SERP1 reintroduction reverses the hypoxic cell death elicited by miR-124, indicating the importance of SERP1 in promoting tumor cell survival. In support of our experimental data, we observed a significant correlation between high SERP1 levels and poor patient outcome in glioblastoma patients. Collectively, among the many pro-tumorigeneic properties of miR-124 repression in glioblastoma, we delineated a novel role in promoting tumor cell survival under stressful microenvironments, thereby supporting tumor progression.Oncogene advance online publication, 23 June 2014; doi:10.1038/onc.2014.168.
    Preview · Article · Jun 2014 · Oncogene

Publication Stats

1k Citations
344.11 Total Impact Points

Institutions

  • 2015
    • University of Michigan
      Ann Arbor, Michigan, United States
    • Institut Claudius Regaud
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2013-2015
    • Memorial Sloan-Kettering Cancer Center
      • Division of Cancer Biology & Genetics
      New York, New York, United States
  • 2011-2015
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2014
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 2009-2014
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Department of Radiation Oncology
      • • Department of Medicine
      Philadelphia, Pennsylvania, United States
  • 2010
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
  • 2004-2008
    • University of Pittsburgh
      • • Department of Pathology
      • • Department of Neurobiology
      Pittsburgh, Pennsylvania, United States
  • 2007
    • National Institute of Radiological Sciences
      • Molecular Imagining Center
      Chiba-shi, Chiba-ken, Japan
  • 2006
    • Bangalore University
      Bengalūru, Karnātaka, India