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GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth

Bayin, N S; Frenster, J D; Kane, J R; Rubenstein, J; Modrek, A S; Baitalmal, R; Dolgalev, I; Rudzenski, K; Scarabottolo, L; Crespi, D; Redaelli, L; Snuderl, M; Golfinos, J G; Doyle, W; Pacione, D; Parker, E C; Chi, A S; Heguy, A; MacNeil, D J; Shohdy, N; Zagzag, D; Placantonakis, D G
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.
PMCID:5117849
PMID: 27775701
ISSN: 2157-9024
CID: 2281812

RNA-Seq reveals distinct transcriptomes in normal and trisomic human pre-implantation embryos [Meeting Abstract]

Licciardi, F; Kramer, Y; Zhang, Y; Tsirigos, A; Lhakhang, T; Heguy, A
Study question: What do RNA seq-profiles tell us about gene activity in preimplantation embryos known to be normal vs. trisomic for chromosomes 21, 18, 15 and 22. Summary answer: RNA-Seq profiles are karyotype-dependent and appear to correlate with viability. X and Y transcription is surprisingly active at the preimplantation stage. What is known already: Embryonic karyotypic abnormalities are the most common cause of implantation failure and miscarriage. Some such embryos can progress to viability as evidenced by the birth of children with Trisomy 21, 18 and 15. An abnormal karyotype dictates developmental aberrations, and for these differences to affect phenotype, variations in gene expression must occur in the developing embryo. We set out to determine if such changes could be identified in embryos as early as the pre-implantation stage. Study design, size, duration: We used a cohort of 19 pre-implantation embryos (day 5 and 6 blastocysts); three being normal, five trisomy 15, two trisomy 22, three trisomy 21 and three trisomy 18, and three of unknown karyotype. Participants/materials, setting, methods: After written consent, analysis was performed on high quality embryos that previously underwent trophectoderm biopsy with array comparative genomic hybridization (aCGH) or next generation sequencing (NGS) for 24-chromosome aneuploidy screening and vitrified. Blastocysts were lysed immediately after thawing, and cDNA was synthesized and amplified, followed by RNA-Seq library preparation for deep Illuminabased sequencing. Sex and chromosomal aneuploidy were used as parameters for comparative analysis using a bioinformatics pipeline using a sensitivity of 0.05. Main results and the role of chance: Principal Component analysis (PCA) revealed that normal embryos clustered in proximity to trisomies 21 and 18, while 15 and 22 clustered separately. This suggested that early gene expression may correlate with viability. PCA did not distinguish between male and female embryos. Differential gene expression was calculated using DESEQ2, an R package that estimates the variance-mean dependence and tests for differential expression using a model using the negative binomial distribution. A comparison of sex-specific gene expression showed that the top differentially expressed genes were on the sex chromosomes, including various Y-linked transcription factors, helicases, and ribosomal proteins, as well as a testis-specific regulatory transcript, and >200 X-chromosome genes. Trisomy 21 embryos were the closest to normal embryos, with only 3 genes on chromosome 21 expressed more highly in the trisomic embryos. In contrast, trisomy 22 embryos (non viable), had 684 differentially expressed genes, 32 of which on chromosome 22. Trisomy 18 embryos had only one highly expressed significant gene, and it is located on chromosome 18. Trisomy 15 embryos had 829 differentially expressed genes, of which 83 were in chromosome 15. Our results suggest that the less viable trisomies have bigger gene expression differences, even at this very early stage. Limitations, reasons for caution: While the karyotypes were analyzed by stringent methods, embryos may have had elements of mosaicism or chromosomal structural abnormalities. The genes identified by RNA-Seq need to be validated using orthogonal methods. Wider implications of the findings: We have expanded the knowledge of the transcriptome of the human pre-implantation embryo as they relate to aneuploidy and sex. This information can now be used to further our understanding of early embryonic development and stem cell biology, and to identify biomarkers for non-invasive preimplantation genomic screening
EMBASE:615297935
ISSN: 1460-2350
CID: 2533772

Clinical, Pathological and Molecular Characteristics of Infiltrating Astrocytomas of the Spinal cord [Meeting Abstract]

Thomas, Cheddhi; Hidalgo, Eveline; Dastagirzada, Yosef; Serrano, Jonathan; Wang, Shiyang; Kannan, Kasthuri; Capper, David; Hovestadt, Volker; Pfister, Stefan; Jones, David; Sill, Martin; von Deimling, Andreas; Heguy, Adriana; Gardner, Sharon; Allen, Jeffrey; Zagzag, David; Karajannis, Matthias; Snuderl, Matija
ISI:000377665000019
ISSN: 0022-3069
CID: 2687522

Exome Sequencing Reveals Activation of STAT3 Pathway in non-VHL Tumors in Hemangioblastoma [Meeting Abstract]

Kannan, Kasthuri; Snuderl, Matija; Mashiach, Elad; Baitalmal, Rabaa; Aminova, Olga; Zappile, Paul; Karajannis, Matthias; Heguy, Adriana; Zagzag, David
ISI:000377665000041
ISSN: 0022-3069
CID: 2687532

ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMAS: A CLINICOPATHOLOGIC AND MOLECULAR PROFILE [Meeting Abstract]

Segal, Devorah; Thomas, Cheddhi; Bowman, Christopher; Kannan, Kasthuri; Wang, Shiyang; Heguy, Adriana; Liechty, Benjamin; Jones, David; Hovestadt, Volker; Pfister, Stefan; Karajannis, Matthias; Snuderl, Matija
ISI:000379749000302
ISSN: 1523-5866
CID: 2687542

RNASEQ IDENTIFIES DIFFERENTIAL EXPRESSION OF PLATELET TRANSCRIPTS IN SUBJECTS WITH PERIPHERAL ARTERY DISEASE [Meeting Abstract]

Montenont, Emilie; Lhakhan, Tenzin; Newman, Jonathan D.; Bissoon, Edna; Cambria, Matthew; Rubin, Maya; Suarez, Yajaira; Heguy, Adriana; Tsirigos, Aristotelis; Berger, Jeffrey S.
ISI:000375188703085
ISSN: 0735-1097
CID: 2962392

Prefrontal neuronal integrity predicts symptoms and cognition in schizophrenia and is sensitive to genetic heterogeneity

Malaspina, Dolores; Kranz, Thorsten M; Heguy, Adriana; Harroch, Sheila; Mazgaj, Robert; Rothman, Karen; Berns, Adam; Hasan, Sumya; Antonius, Daniel; Goetz, Raymond; Lazar, Mariana; Chao, Moses V; Gonen, Oded
Schizophrenia is a genetically complex syndrome with substantial inter-subject variability in multiple domains. Person-specific measures to resolve its heterogeneity could focus on the variability in prefrontal integrity, which this study indexed as relative rostralization within the anterior cingulate cortex (ACC). Twenty-two schizophrenia cases and 11 controls underwent rigorous diagnostic procedures, symptom assessments (PANSS, Deficit Syndrome Scale) and intelligence testing. All underwent multivoxel MRSI at 3T to measure concentrations of the neuronal-specific biomarker N-acetylaspartate (NAA) in all of the voxels of the ACC. The concentrations of NAA were separately calculated and then compared across the rostral and caudal subregions to generate a rostralization ratio, which was examined with respect to the study measures and to which cases carried a missense coding polymorphism in PTPRG, SCL39A13, TGM5, NTRK1 or ARMS/KIDINS220. Rostralization significantly differed between cases and controls (chi2=18.40, p<.0001). In cases, it predicted verbal intelligence (r=.469, p=.043) and trait negative symptoms (diminished emotional range (r=-.624, p=.010); curbed interests, r=-.558, p=.025). Rostralization was similar to controls for missense coding variants in TGM5 and was significantly greater than controls for the PTPRG variant carrier. This is the first study examining the utility of MRS metrics in describing pathological features at both group and person-specific levels. Rostralization predicted core illness features and differed based on which signaling genes were disrupted. While future studies in larger populations are needed, ACC rostralization appears to be a promising measure to reduce the heterogeneity of schizophrenia for genetic research and selecting cases for treatment studies.
PMCID:4894496
PMID: 26925801
ISSN: 1573-2509
CID: 2009242

Mammary stem cell modulation of wildtype and Trp53 null stem cells by CAPE (caffeic acid phenethyl ester), a potential therapeutic agent [Meeting Abstract]

Omene, C; Patel, M; Kannan, K; Heguy, A; Barcellos-Hoff, MH
ISI:000375622404173
ISSN: 1538-7445
CID: 2688372

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Diamond, Eli L; Durham, Benjamin H; Haroche, Julien; Yao, Zhan; Ma, Jing; Parikh, Sameer A; Wang, Zhaoming; Choi, John; Kim, Eunhee; Cohen-Aubart, Fleur; Lee, Stanley Chun-Wei; Gao, Yijun; Micol, Jean-Baptiste; Campbell, Patrick; Walsh, Michael P; Sylvester, Brooke; Dolgalev, Igor; Aminova, Olga; Heguy, Adriana; Zappile, Paul; Nakitandwe, Joy; Ganzel, Chezi; Dalton, James D; Ellison, David W; Estrada-Veras, Juvianee; Lacouture, Mario; Gahl, William A; Stephens, Philip J; Miller, Vincent A; Ross, Jeffrey S; Ali, Siraj M; Briggs, Samuel R; Fasan, Omotayo; Block, Jared; Heritier, Sebastien; Donadieu, Jean; Solit, David B; Hyman, David M; Baselga, Jose; Janku, Filip; Taylor, Barry S; Park, Christopher Y; Amoura, Zahir; Dogan, Ahmet; Emile, Jean-Francois; Rosen, Neal; Gruber, Tanja A; Abdel-Wahab, Omar
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.
PMCID:4744547
PMID: 26566875
ISSN: 2159-8290
CID: 1834902

Advancing methylation profiling in neuropathology: Diagnosis and clinical management [Meeting Abstract]

Kannan, Kasthuri S; Tsirigos, Aristotelis; Serrano, Jonathan; Forrester, Lynn Ann; Faustin, Arline; Thomas, Cheddhi; Capper, David; Hovestadt, Volker; Pfister, Stefan M; Jones, David TW; Sill, Martin; Schrimpf, Daniel; von Deimling, Andreas; Heguy, Adriana; Gardner, Sharon L; Allen, Jeffrey; Hedvat, Cyrus; Zagzag, David; Snuderl, Matija; Karajannis, Matthias A
ISI:000369082700032
ISSN: 1557-3265
CID: 2687512