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The bone marrow microenvironment at single-cell resolution
Tikhonova, Anastasia N; Dolgalev, Igor; Hu, Hai; Sivaraj, Kishor K; Hoxha, Edlira; Cuesta-DomÃnguez, Ãlvaro; Pinho, Sandra; Akhmetzyanova, Ilseyar; Gao, Jie; Witkowski, Matthew; Guillamot, Maria; Gutkin, Michael C; Zhang, Yutong; Marier, Christian; Diefenbach, Catherine; Kousteni, Stavroula; Heguy, Adriana; Zhong, Hua; Fooksman, David R; Butler, Jason M; Economides, Aris; Frenette, Paul S; Adams, Ralf H; Satija, Rahul; Tsirigos, Aristotelis; Aifantis, Iannis
The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.
PMID: 30971824
ISSN: 1476-4687
CID: 3809302
The Ancient Origins of Neural Substrates for Land Walking
Jung, Heekyung; Baek, Myungin; D'Elia, Kristen P; Boisvert, Catherine; Currie, Peter D; Tay, Boon-Hui; Venkatesh, Byrappa; Brown, Stuart M; Heguy, Adriana; Schoppik, David; Dasen, Jeremy S
Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
PMCID:5808577
PMID: 29425489
ISSN: 1097-4172
CID: 2948352
Synthesis, debugging, and effects of synthetic chromosome consolidation: synVI and beyond
Mitchell, Leslie A; Wang, Ann; Stracquadanio, Giovanni; Kuang, Zheng; Wang, Xuya; Yang, Kun; Richardson, Sarah; Martin, J Andrew; Zhao, Yu; Walker, Roy; Luo, Yisha; Dai, Hongjiu; Dong, Kang; Tang, Zuojian; Yang, Yanling; Cai, Yizhi; Heguy, Adriana; Ueberheide, Beatrix; Fenyo, David; Dai, Junbiao; Bader, Joel S; Boeke, Jef D
We describe design, rapid assembly, and characterization of synthetic yeast Sc2.0 chromosome VI (synVI). A mitochondrial defect in the synVI strain mapped to synonymous coding changes within PRE4 (YFR050C), encoding an essential proteasome subunit; Sc2.0 coding changes reduced Pre4 protein accumulation by half. Completing Sc2.0 specifies consolidation of 16 synthetic chromosomes into a single strain. We investigated phenotypic, transcriptional, and proteomewide consequences of Sc2.0 chromosome consolidation in poly-synthetic strains. Another "bug" was discovered through proteomic analysis, associated with alteration of the HIS2 transcription start due to transfer RNA deletion and loxPsym site insertion. Despite extensive genetic alterations across 6% of the genome, no major global changes were detected in the poly-synthetic strain "omics" analyses. This work sets the stage for completion of a designer, synthetic eukaryotic genome.
PMID: 28280154
ISSN: 1095-9203
CID: 2476892
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
Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
Danussi, Carla; Bose, Promita; Parthasarathy, Prasanna T; Silberman, Pedro C; Van Arnam, John S; Vitucci, Mark; Tang, Oliver Y; Heguy, Adriana; Wang, Yuxiang; Chan, Timothy A; Riggins, Gregory J; Sulman, Erik P; Lang, Frederick; Creighton, Chad J; Deneen, Benjamin; Miller, C Ryan; Picketts, David J; Kannan, Kasthuri; Huse, Jason T
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts.
PMCID:5849741
PMID: 29535300
ISSN: 2041-1723
CID: 2992712
Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma
Snuderl, Matija; Kannan, Kasthuri; Pfaff, Elke; Wang, Shiyang; Stafford, James M; Serrano, Jonathan; Heguy, Adriana; Ray, Karina; Faustin, Arline; Aminova, Olga; Dolgalev, Igor; Stapleton, Stacie L; Zagzag, David; Chiriboga, Luis; Gardner, Sharon L; Wisoff, Jeffrey H; Golfinos, John G; Capper, David; Hovestadt, Volker; Rosenblum, Marc K; Placantonakis, Dimitris G; LeBoeuf, Sarah E; Papagiannakopoulos, Thales Y; Chavez, Lukas; Ahsan, Sama; Eberhart, Charles G; Pfister, Stefan M; Jones, David T W; Karajannis, Matthias A
Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
PMCID:6054684
PMID: 30030436
ISSN: 2041-1723
CID: 3202352
Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal
Azzouz, Doua; Omarbekova, Aidana; Heguy, Adriana; Schwudke, Dominik; Gisch, Nicolas; Rovin, Brad H; Caricchio, Roberto; Buyon, Jill P; Alekseyenko, Alexander V; Silverman, Gregg J
BACKGROUND/PURPOSE/OBJECTIVE:To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity. METHODS:In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts. RESULTS:strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts. CONCLUSION/CONCLUSIONS:These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.
PMID: 30782585
ISSN: 1468-2060
CID: 3686132
Radiotherapy induces responses of lung cancer to CTLA-4 blockade
Formenti, Silvia C; Rudqvist, Nils-Petter; Golden, Encouse; Cooper, Benjamin; Wennerberg, Erik; Lhuillier, Claire; Vanpouille-Box, Claire; Friedman, Kent; Ferrari de Andrade, Lucas; Wucherpfennig, Kai W; Heguy, Adriana; Imai, Naoko; Gnjatic, Sacha; Emerson, Ryan O; Zhou, Xi Kathy; Zhang, Tuo; Chachoua, Abraham; Demaria, Sandra
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4-6. The latter is essential for achieving abscopal responses in murine cancers6. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.
PMID: 30397353
ISSN: 1546-170x
CID: 3455792
Digital spatial profiling to predict recurrence in grade 3 stage I lung adenocarcinoma
Chang, Stephanie H; Mezzano-Robinson, Valeria; Zhou, Hua; Moreira, Andre; Pillai, Raymond; Ramaswami, Sitharam; Loomis, Cynthia; Heguy, Adriana; Tsirigos, Aristotelis; Pass, Harvey I
OBJECTIVE:Early-stage lung adenocarcinoma is treated with local therapy alone, although patients with grade 3 stage I lung adenocarcinoma have a 50% 5-year recurrence rate. Our objective is to determine if analysis of the tumor microenvironment can create a predictive model for recurrence. METHODS:Thirty-four patients with grade 3 stage I lung adenocarcinoma underwent surgical resection. Digital spatial profiling was used to perform genomic (n = 31) and proteomic (n = 34) analyses of pancytokeratin positive and negative tumor cells. K-means clustering was performed on the top 50 differential genes and top 20 differential proteins, with Kaplan-Meier recurrence curves based on patient clustering. External validation of high-expression genes was performed with Kaplan-Meier plotter. RESULTS:There were no significant clinicopathologic differences between patients who did (n = 14) and did not (n = 20) have recurrence. Median time to recurrence was 806 days; median follow-up with no recurrence was 2897 days. K-means clustering of pancytokeratin positive genes resulted in a model with a Kaplan-Meier curve with concordance index of 0.75. K-means clustering for pancytokeratin negative genes was less successful at differentiating recurrence (concordance index 0.6). Genes upregulated or downregulated for recurrence were externally validated using available public databases. Proteomic data did not reach statistical significance but did internally validate the genomic data described. CONCLUSIONS:Genomic difference in lung adenocarcinoma may be able to predict risk of recurrence. After further validation, stratifying patients by this risk may help guide who will benefit from adjuvant therapy.
PMID: 37890657
ISSN: 1097-685x
CID: 5620342
Cellular dynamics in pig-to-human kidney xenotransplantation
Pan, Wanqing; Zhang, Weimin; Zheng, Binghan; Camellato, Brendan R; Stern, Jeffrey; Lin, Ziyan; Khodadadi-Jamayran, Alireza; Kim, Jacqueline; Sommer, Philip; Khalil, Karen; Weldon, Elaina; Bai, Jiangshan; Zhu, Yinan; Meyn, Peter; Heguy, Adriana; Mangiola, Massimo; Griesemer, Adam; Keating, Brendan J; Montgomery, Robert A; Xia, Bo; Boeke, Jef D
BACKGROUND:Xenotransplantation of genetically engineered porcine organs has the potential to address the challenge of organ donor shortage. Two cases of porcine-to-human kidney xenotransplantation were performed, yet the physiological effects on the xenografts and the recipients' immune responses remain largely uncharacterized. METHODS:We performed single-cell RNA sequencing (scRNA-seq) and longitudinal RNA-seq analyses of the porcine kidneys to dissect xenotransplantation-associated cellular dynamics and xenograft-recipient interactions. We additionally performed longitudinal scRNA-seq of the peripheral blood mononuclear cells (PBMCs) to detect recipient immune responses across time. FINDINGS/RESULTS:Although no hyperacute rejection signals were detected, scRNA-seq analyses of the xenografts found evidence of endothelial cell and immune response activation, indicating early signs of antibody-mediated rejection. Tracing the cells' species origin, we found human immune cell infiltration in both xenografts. Human transcripts in the longitudinal bulk RNA-seq revealed that human immune cell infiltration and the activation of interferon-gamma-induced chemokine expression occurred by 12 and 48 h post-xenotransplantation, respectively. Concordantly, longitudinal scRNA-seq of PBMCs also revealed two phases of the recipients' immune responses at 12 and 48-53 h. Lastly, we observed global expression signatures of xenotransplantation-associated kidney tissue damage in the xenografts. Surprisingly, we detected a rapid increase of proliferative cells in both xenografts, indicating the activation of the porcine tissue repair program. CONCLUSIONS:Longitudinal and single-cell transcriptomic analyses of porcine kidneys and the recipient's PBMCs revealed time-resolved cellular dynamics of xenograft-recipient interactions during xenotransplantation. These cues can be leveraged for designing gene edits and immunosuppression regimens to optimize xenotransplantation outcomes. FUNDING/BACKGROUND:This work was supported by NIH RM1HG009491 and DP5OD033430.
PMID: 38776915
ISSN: 2666-6340
CID: 5654702