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1دورية أكاديمية
المؤلفون: Huang, Miller, Fang, Wanqi, Farrel, Alvin, Li, Linwei, Chronopoulos, Antonios, Nasholm, Nicole, Cheng, Bo, Zheng, Tina, Yoda, Hiroyuki, Barata, Megumi J, Porras, Tania, Miller, Matthew L, Zhen, Qiqi, Ghiglieri, Lisa, McHenry, Lauren, Wang, Linyu, Asgharzadeh, Shahab, Park, JinSeok, Gustafson, W Clay, Matthay, Katherine K, Maris, John M, Weiss, William A
المصدر: Cell Reports. 43(3)
مصطلحات موضوعية: Biological Sciences, Stem Cell Research, Neuroblastoma, Pediatric Cancer, Neurosciences, Cancer, Pediatric, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Humans, Anaplastic Lymphoma Kinase, Cell Adhesion Molecules, Cell Line, Tumor, N-Myc Proto-Oncogene Protein, Receptor Protein-Tyrosine Kinases, Wnt Signaling Pathway, ALK, CP: Cancer, MYCN, POSTN, WNT, human pluripotent stem cells, neuroblastoma, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
الوصف: Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.
وصف الملف: application/pdf
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2دورية أكاديمية
المؤلفون: Kuzuoglu-Ozturk, Duygu, Aksoy, Ozlem, Schmidt, Christin, Lea, Robin, Larson, Jon D, Phelps, Ryan RL, Nasholm, Nicole, Holt, Megan, Contreras, Adrian, Huang, Miller, Wong-Michalak, Shannon, Shao, Hao, Wechsler-Reya, Robert, Phillips, Joanna J, Gestwicki, Jason E, Ruggero, Davide, Weiss, William A
المصدر: Cancer Research. 83(1)
مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Orphan Drug, Brain Cancer, Brain Disorders, Pediatric, Pediatric Cancer, Neurosciences, Rare Diseases, Genetics, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Child, Humans, Mice, Animals, Proto-Oncogene Proteins c-myc, Medulloblastoma, Eukaryotic Initiation Factor-4E, Disease Models, Animal, Cerebellar Neoplasms, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
الوصف: Deregulation of neuroblastoma-derived myc (N-myc) is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data revealed that N-myc regulates the expression of specific components (∼5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic.SignificanceTranslatome analysis in medulloblastoma shows that N-myc drives selective translation of transcripts that promote protein homeostasis and that represent new therapeutic vulnerabilities.
وصف الملف: application/pdf
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3دورية أكاديمية
المؤلفون: Becklin, Kelsie L, Draper, Garrett M, Madden, Rebecca A, Kluesner, Mitchell G, Koga, Tomoyuki, Huang, Miller, Weiss, William A, Spector, Logan G, Largaespada, David A, Moriarity, Branden S, Webber, Beau R
المصدر: The CRISPR Journal. 5(4)
مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Bioengineering, Regenerative Medicine, Biotechnology, Human Genome, Stem Cell Research, Rare Diseases, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Cancer, CRISPR-Cas Systems, Gene Editing, Humans, Induced Pluripotent Stem Cells, Neoplasms
الوصف: Advances in genome and tissue engineering have spurred significant progress and opportunity for innovation in cancer modeling. Human induced pluripotent stem cells (iPSCs) are an established and powerful tool to study cellular processes in the context of disease-specific genetic backgrounds; however, their application to cancer has been limited by the resistance of many transformed cells to undergo successful reprogramming. Here, we review the status of human iPSC modeling of solid tumors in the context of genetic engineering, including how base and prime editing can be incorporated into "bottom-up" cancer modeling, a term we coined for iPSC-based cancer models using genetic engineering to induce transformation. This approach circumvents the need to reprogram cancer cells while allowing for dissection of the genetic mechanisms underlying transformation, progression, and metastasis with a high degree of precision and control. We also discuss the strengths and limitations of respective engineering approaches and outline experimental considerations for establishing future models.
وصف الملف: application/pdf
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4دورية أكاديمية
المؤلفون: Huang, Miller, Tailor, Jignesh, Zhen, Qiqi, Gillmor, Aaron H, Miller, Matthew L, Weishaupt, Holger, Chen, Justin, Zheng, Tina, Nash, Emily K, McHenry, Lauren K, An, Zhenyi, Ye, Fubaiyang, Takashima, Yasuhiro, Clarke, James, Ayetey, Harold, Cavalli, Florence MG, Luu, Betty, Moriarity, Branden S, Ilkhanizadeh, Shirin, Chavez, Lukas, Yu, Chunying, Kurian, Kathreena M, Magnaldo, Thierry, Sevenet, Nicolas, Koch, Philipp, Pollard, Steven M, Dirks, Peter, Snyder, Michael P, Largaespada, David A, Cho, Yoon Jae, Phillips, Joanna J, Swartling, Fredrik J, Morrissy, A Sorana, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Smith, Austin, Weiss, William A
المصدر: Cell Stem Cell. 25(3)
مصطلحات موضوعية: Medical Biotechnology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Brain Disorders, Regenerative Medicine, Pediatric, Pediatric Cancer, Stem Cell Research, Transplantation, Biotechnology, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Cancer, Neurosciences, Stem Cell Research - Nonembryonic - Non-Human, Brain Cancer, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, Animals, Basal Cell Nevus Syndrome, Brain Neoplasms, Carcinogenesis, DEAD-box RNA Helicases, Disease Models, Animal, Genetic Engineering, Genetic Predisposition to Disease, Humans, Medulloblastoma, Mice, Mice, SCID, N-Myc Proto-Oncogene Protein, Neoplasm Proteins, Neural Stem Cells, Neuroepithelial Cells, Patched-1 Receptor, Pluripotent Stem Cells, Stem Cell Transplantation, Transplantation, Heterologous, SHH, human pluripotent stem cells, medulloblastoma, neuroepithelial stem cells, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
الوصف: Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predisposed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
وصف الملف: application/pdf
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5دورية أكاديمية
المؤلفون: Qadeer, Zulekha, Westelman, Samantha, Johnson, Mackenzie, Grele, Shane, Hou, Elise, Hendrikse, Liam, Wang, Linyu, Husain, Sarah, Beytagh, Mary Clare, Schmidt, Christin, Huang, Miller, Taylor, Michael, Weiss, William
المصدر: Neuro-Oncology ; volume 25, issue Supplement_1, page i62-i63 ; ISSN 1522-8517 1523-5866
مصطلحات موضوعية: Cancer Research, Neurology (clinical), Oncology
الوصف: Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at <50%, few recurrent mutations, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some MB tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We hypothesize that the TGFβ pathway and MYC contribute to the intrinsic resistance of G3MB through deregulation of key genes and pathways. We previously established humanized models for SHHMB by introducing MYCN or PTCH1 deletions into neuroepithelial stem cells (NESC) derived from normal human induced pluripotent stem cells (hIPSCs). In this study, we transduced NESCs with TGFb effectors activated in G3MB alone and/or in combination with MYC, prioritizing combinations observed in patients. Excitingly, both MYC and TGFβ effectors drove tumor formation in vivo with the combination of TGFβ effectors with MYC leading to more aggressive tumors. We next found that NESCs expressing MYC with either TGFβR1 or TGFβ1 showed resistance to clinical TGFβR1 inhibitors, compared to cells driven by either TGFβR1 or TGFβ1 alone. To decipher mechanisms of resistance, we integrated CUT&RUN to probe for MYC genomic localization and relevant histone PTMs with RNA-seq analysis and discovered a subset of genes upregulated in MYC and TGFb-driven lines that are targets of the histone demethylase KDM2B. Loss of function mutations in KDM2B occur in G3MB patients, indicating that KDM2B deregulated genes are critical in G3MB. We postulate that epigenetic remodeling via MYC and recruitment of other MYC-interacting cofactors to KDM2B targets culminates in transcriptional changes that lead to aggressive disease. Overall, our studies provide important insight on identifying new therapeutic avenues for patients with MYC and TGFβ driven G3MB.
الإتاحة: https://doi.org/10.1093/neuonc/noad073.240Test
https://academic.oup.com/neuro-oncology/article-pdf/25/Supplement_1/i62/50575236/noad073.240.pdfTest -
6دورية أكاديمية
المؤلفون: Huang, Miller, Miller, Matthew L, McHenry, Lauren K, Zheng, Tina, Zhen, Qiqi, Ilkhanizadeh, Shirin, Conklin, Bruce R, Bronner, Marianne E, Weiss, William A
المصدر: Scientific reports. 6(1)
مصطلحات موضوعية: Cells, Cultured, Pluripotent Stem Cells, Neural Crest, Humans, Tretinoin, Homeodomain Proteins, Bone Morphogenetic Proteins, Signal Transduction, Cell Differentiation, Gene Expression Regulation, Developmental, Biomarkers, Cells, Cultured, Gene Expression Regulation, Developmental, Stem Cell Research, Clinical Research, Rare Diseases, Regenerative Medicine, Dental/Oral and Craniofacial Disease, Neurosciences, Pediatric, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Embryonic - Human, 1.1 Normal biological development and functioning, Generic Health Relevance, Biochemistry and Cell Biology, Other Physical Sciences
الوصف: Neural crest cells (NCC) are stem cells that generate different lineages, including neuroendocrine, melanocytic, cartilage, and bone. The differentiation potential of NCC varies according to the level from which cells emerge along the neural tube. For example, only anterior "cranial" NCC form craniofacial bone, whereas solely posterior "trunk" NCC contribute to sympathoadrenal cells. Importantly, the isolation of human fetal NCC carries ethical and scientific challenges, as NCC induction typically occur before pregnancy is detectable. As a result, current knowledge of NCC biology derives primarily from non-human organisms. Important differences between human and non-human NCC, such as expression of HNK1 in human but not mouse NCC, suggest a need to study human NCC directly. Here, we demonstrate that current protocols to differentiate human pluripotent stem cells (PSC) to NCC are biased toward cranial NCC. Addition of retinoic acid drove trunk-related markers and HOX genes characteristic of a posterior identity. Subsequent treatment with bone morphogenetic proteins (BMPs) enhanced differentiation to sympathoadrenal cells. Our approach provides methodology for detailed studies of human NCC, and clarifies roles for retinoids and BMPs in the differentiation of human PSC to trunk NCC and to sympathoadrenal lineages.
الوصول الحر: https://escholarship.org/uc/item/43g0g250Test
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7دورية أكاديمية
المؤلفون: Miyaoka, Yuichiro, Chan, Amanda H, Judge, Luke M, Yoo, Jennie, Huang, Miller, Nguyen, Trieu D, Lizarraga, Paweena P, So, Po-Lin, Conklin, Bruce R
المصدر: Nature Methods. 11(3)
مصطلحات موضوعية: Biological Sciences, Generic health relevance, Anti-Bacterial Agents, Base Composition, Cell Line, Cloning, Molecular, Cytological Techniques, Genome, Human, Humans, Induced Pluripotent Stem Cells, Mutation, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
الوصف: Precise editing of human genomes in pluripotent stem cells by homology-driven repair of targeted nuclease-induced cleavage has been hindered by the difficulty of isolating rare clones. We developed an efficient method to capture rare mutational events, enabling isolation of mutant lines with single-base substitutions without antibiotic selection. This method facilitates efficient induction or reversion of mutations associated with human disease in isogenic human induced pluripotent stem cells.
الوصول الحر: https://escholarship.org/uc/item/3bx0d4x4Test
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8دورية أكاديمية
المؤلفون: Ilkhanizadeh, Shirin, Lau, Jasmine, Huang, Miller, Foster, Daniel J, Wong, Robyn, Frantz, Aaron, Wang, Susan, Weiss, William A, Persson, Anders I
المصدر: ADVANCES IN CANCER RESEARCH, VOL 121. 121(Neoplasia 10 11 2008)
مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Orphan Drug, Cancer, Rare Diseases, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Neurosciences, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Brain Disorders, Neurological, Animals, Cell Differentiation, Cell Lineage, Cell Transformation, Neoplastic, Glioma, Humans, Molecular Targeted Therapy, Neural Stem Cells, Neuroglia, Brain, Glioblastoma, Neural stem cell, Oligodendrocyte progenitor cell, Oncology & Carcinogenesis, Oncology and carcinogenesis
الوصف: Glioma is the most common primary malignant brain tumor and arises throughout the central nervous system. Recent focus on stem-like glioma cells has implicated neural stem cells (NSCs), a minor precursor population restricted to germinal zones, as a potential source of gliomas. In this review, we focus on the relationship between oligodendrocyte progenitor cells (OPCs), the largest population of cycling glial progenitors in the postnatal brain, and gliomagenesis. OPCs can give rise to gliomas, with signaling pathways associated with NSCs also playing key roles during OPC lineage development. Gliomas can also undergo a switch from progenitor- to stem-like phenotype after therapy, consistent with an OPC-origin even for stem-like gliomas. Future in-depth studies of OPC biology may shed light on the etiology of OPC-derived gliomas and reveal new therapeutic avenues.
وصف الملف: application/pdf
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9دورية أكاديمية
المؤلفون: Huang, Miller, Weiss, William A
المصدر: Cold Spring Harbor Perspectives in Medicine. 3(10)
مصطلحات موضوعية: Rare Diseases, Cancer, Pediatric Cancer, Pediatric, Neurosciences, Genetics, Neuroblastoma, Antigens, Neoplasm, Apoptosis, Cell Cycle, Cell Proliferation, Gene Amplification, Gene Expression, Genes, myc, Genetic Markers, Humans, Mutation, N-Myc Proto-Oncogene Protein, Neoplasm Metastasis, Neovascularization, Pathologic, Nuclear Proteins, Oncogene Proteins, Protein Stability, Risk Factors, Transcription, Genetic, Medical Biochemistry and Metabolomics, Medical Microbiology, Medical Physiology
الوصف: Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to originate from undifferentiated neural crest cells. Amplification of the MYC family member, MYCN, is found in ∼25% of cases and correlates with high-risk disease and poor prognosis. Currently, amplification of MYCN remains the best-characterized genetic marker of risk in neuroblastoma. This article reviews roles for MYCN in neuroblastoma and highlights recent identification of other driver mutations. Strategies to target MYCN at the level of protein stability and transcription are also reviewed.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/0j71m4wrTest
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10دورية أكاديمية
المؤلفون: Sun, Yaping, Dong, Zhiqiang, Jin, Taihao, Ang, Kean-Hooi, Huang, Miller, Haston, Kelly, Peng, Jisong, Zhong, Tao, Weiss, William, Guo, Su, Finkbeiner, Steven, Jan, Lily, Arkin, Michelle
مصطلحات موضوعية: E. coli, Mouse, Zebrafish, cellular differentiation, chemical genetics, dopaminergic neurons, pluripotent stem cells, small molecule tool, Animals, Cell Differentiation, Cell Lineage, Cells, Cultured, High-Throughput Screening Assays, Ivermectin, Mice, Neurons, Pluripotent Stem Cells, Receptors, GABA-A
الوصف: Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectins pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. DOI:http://dx.doi.org/10.7554/eLife.00508.001Test.
وصف الملف: application/pdf
