Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

Bosse, Kristopher R.; Raman, Pichai; Zhu, Zhongyu; Lane, Maria; Martı́nez, Daniel; Heitzeneder, Sabine; Rathi, Komal S.; Kendsersky, Nathan M.; Randall, Michael P.; Donovan, Laura; Morrissy, A. Sorana; Sussman, Robyn T.; Zhelev, Doncho V.; Yang, Feng; Wang, Yanping; Hwang, J.; Lopez, Gonzalo; Harenza, Jo Lynne; Wei, Jun S.; Pawel, Bruce; Bhatti, Tricia R.; Santi, Mariarita; Ganguly, Arupa; Khan, Javed; Marra, Marco A.; Taylor, Michael D.; Dimitrov, Dimiter S.; Mackall, Crystal L.; Maris, John M.

doi:10.1016/j.ccell.2017.08.003

Cited by 170 publications

(236 citation statements)

References 41 publications

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“…Chromatin immunoprecipitation was performed on adherent cells as described in Bosse et al, 2017(Bosse et al 2017). Of note, a different MYCN antibody was used than listed in Bosse et al, 2017 (Santa Cruz B8.4B, sc-53993).…”

Section: Mycn Chip-seq: Kelly and Ngp Cell Linesmentioning

confidence: 99%

Epigenomic profiling of neuroblastoma cell lines

Upton

Modi

Patel

et al. 2019

Preprint

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AbstractUnderstanding the aberrant transcriptional landscape of neuroblastoma is necessary to provide insight to the underlying influences of the initiation, progression and persistence of this developmental cancer. Here, we present chromatin immunoprecipitation sequencing (ChIP-Seq) data for the oncogenic transcription factors, MYCN and MYC, as well as regulatory histone marks H3K4me1, H3K4me3, H3K27Ac, and H3K27me3 in ten commonly used human neuroblastoma-derived cell line models. In addition, for all of the profiled cell lines we provide ATAC-Seq as a measure of open chromatin. We validate specificity of global MYCN occupancy in MYCN amplified cell lines and functional redundancy of MYC occupancy in MYCN non-amplified cell lines. Finally, we show with H3K27Ac ChIP-Seq that these cell lines retain expression of key neuroblastoma super-enhancers (SE). We anticipate this dataset, coupled with available transcriptomic profiling on the same cell lines, will enable the discovery of novel gene regulatory mechanisms in neuroblastoma.

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Section: Mycn Chip-seq: Kelly and Ngp Cell Linesmentioning

confidence: 99%

Epigenomic profiling of neuroblastoma cell lines

Upton

Modi

Patel

et al. 2019

Preprint

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“…Moreover, analysis of ChIP-Seq data found that MYCN binds to the promoter of PBK in neuroblastoma cell lines, and is accompanied by the active enhancer histone mark, H3K27Ac ( Fig. 6H) (20), suggesting direct transcriptional upregulation of PBK by MYCN.…”

Section: Two Neuroblastoma Oncogenes Lin28b and Mycn Regulate The Ementioning

confidence: 94%

“…(13) PBK promoter luciferase assays were carried out as previously described, with PBK promoter luciferase values normalized to CellTiter-Glo luminescence assay values. (20)…”

Section: 'Utr and Promoter Luciferase Reporter Assaysmentioning

confidence: 99%

“…Kelly MYCN ChIP-Seq was performed and analyzed as previously described (20). For NB-1643 and NGP MYCN and all H3K27Ac ChIP-Seq, cell lines were grown in a 150 mm dish to 60-80% confluency, fixed, and pelleted according to the Active Motif protocol…”

Section: Chromatin Immunoprecipitation Sequencing (Chip-seq)mentioning

confidence: 99%

“…Immunoprecipitations were performed using 30 μg of cell line chromatin and 6 μg of N-Myc antibody (Active Motif # 61185) or 4 μg of H3K27Ac antibody (Active Motif #39133). Libraries were prepared by Active Motif and sequenced on a NextSeq 500 to a depth of ~50 M reads (Jefferson UniversityGenomics Laboratory) and data were analyzed as described previously (20).…”

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confidence: 99%

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LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

Chen

Cox

Annam

et al. 2019

Preprint

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Neuroblastoma is an aggressive pediatric malignancy of the neural crest with suboptimal cure rates and a striking predilection for widespread metastases, underscoring the need to identify novel therapeutic vulnerabilities. We recently identified the RNA binding protein LIN28B as a driver in high-risk neuroblastoma and demonstrated it promotes oncogenic cell proliferation by coordinating a RAN-Aurora kinase A network. Here, we demonstrate that LIN28B influences another key hallmark of cancer, metastatic dissemination. Using a murine xenograft model of neuroblastoma dissemination, we show that LIN28B promotes metastasis. We demonstrate that this is in part due to the effects of LIN28B on self-renewal and migration, providing an understanding of how LIN28B shapes the metastatic phenotype. Our studies reveal that the let-7 family, which LIN28B inhibits, opposes the effects of LIN28B. Next, we identify PDZ Binding Kinase (PBK) as a novel LIN28B target. PBK is a serine/threonine kinase that promotes the proliferation and selfrenewal of neural stem cells and serves as an oncogenic driver in multiple aggressive malignancies. We demonstrate that PBK is both a novel direct target of let-7 and that MYCN regulates PBK expression, thus elucidating two oncogenic drivers that converge on PBK. Functionally, PBK promotes self-renewal and migration, phenocopying LIN28B.Taken together, our findings define a role for LIN28B in neuroblastoma metastasis and define the targetable kinase PBK as a potential novel vulnerability in metastatic neuroblastoma.3

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Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

et al. 2021

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Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion-positive rhabdomyosarcoma, which expresses either PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3-FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient-derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC-209 and PTC-028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

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Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

Cited by 170 publications

References 41 publications

Epigenomic profiling of neuroblastoma cell lines

Epigenomic profiling of neuroblastoma cell lines

LIN28B-PDZ Binding Kinase Signaling Promotes Neuroblastoma Metastasis

Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target

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