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1. Nucleosome fibre topology guides transcription factor binding to enhancers

Author

O’Dwyer, Michael R., Azagury, Meir, Furlong, Katharine, Alsheikh, Amani, Hall-Ponsele, Elisa, Pinto, Hugo, Fyodorov, Dmitry V., Jaber, Mohammad, Papachristoforou, Eleni, Benchetrit, Hana, Ashmore, James, Makedonski, Kirill, Rahamim, Moran, Hanzevacki, Marta, Yassen, Hazar, Skoda, Samuel, Levy, Adi, Pollard, Steven M., Skoultchi, Arthur I., Buganim, Yosef, and Soufi, Abdenour

Published
2024
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6. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Author

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, and Weiss, William A

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Pediatric Cancer, Genetics, Transplantation, Brain Disorders, Pediatric, Regenerative Medicine, Brain Cancer, Stem Cell Research - Nonembryonic - Human, Cancer, Neurosciences, Human Genome, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Rare Diseases, Biotechnology, 2.1 Biological and endogenous factors, 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
Abstract

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.

Published
2019

7. Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells

Author

Bulstrode, Harry, Girdler, Gemma C., Gracia, Tannia, Aivazidis, Alexander, Moutsopoulos, Ilias, Young, Adam M.H., Hancock, John, He, Xiaoling, Ridley, Katherine, Xu, Zhaoyang, Stockley, John H., Finlay, John, Hallou, Clement, Fajardo, Teodoro, Fountain, Daniel M., van Dongen, Stijn, Joannides, Alexis, Morris, Robert, Mair, Richard, Watts, Colin, Santarius, Thomas, Price, Stephen J., Hutchinson, Peter J.A., Hodson, Emma J., Pollard, Steven M., Mohorianu, Irina, Barker, Roger A., Sweeney, Trevor R., Bayraktar, Omer, Gergely, Fanni, and Rowitch, David H.

Published
2022
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11. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion

Author

Gangoso, Ester, Southgate, Benjamin, Bradley, Leanne, Rus, Stefanie, Galvez-Cancino, Felipe, McGivern, Niamh, Güç, Esra, Kapourani, Chantriolnt-Andreas, Byron, Adam, Ferguson, Kirsty M., Alfazema, Neza, Morrison, Gillian, Grant, Vivien, Blin, Carla, Sou, IengFong, Marques-Torrejon, Maria Angeles, Conde, Lucia, Parrinello, Simona, Herrero, Javier, Beck, Stephan, Brandner, Sebastian, Brennan, Paul M., Bertone, Paul, Pollard, Jeffrey W., Quezada, Sergio A., Sproul, Duncan, Frame, Margaret C., Serrels, Alan, and Pollard, Steven M.

Published
2021
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12. The white matter is a pro-differentiative niche for glioblastoma

Author

Brooks, Lucy J., Clements, Melanie P., Burden, Jemima J., Kocher, Daniela, Richards, Luca, Devesa, Sara Castro, Zakka, Leila, Woodberry, Megan, Ellis, Michael, Jaunmuktane, Zane, Brandner, Sebastian, Morrison, Gillian, Pollard, Steven M., Dirks, Peter B., Marguerat, Samuel, and Parrinello, Simona

Published
2021
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17. Specific roles of laminins during vertebrate embryogenesis

Author

Pollard, Steven Michael

Subjects
590, Zoology
Abstract

The notochord is critical for the normal development of vertebrate embryos. Zebrafish mutants, bashful (bal), grumpy (gup) and sleepy (sly) were identified in mutagenesis screens and have defects in notochord differentiation. By positional cloning I identified lama1, encoding Laminin α1, as a candidate for the bal gene. Analysis of mRNA expression, antisense knockdown and sequencing of the mutant lama1, confirmed that mutations in this gene are responsible for the bal phenotype. A similar approach was taken to identify the gup gene. Meiotic mapping identified a region containing lamb1, encoding Laminin β1. Cloning and sequencing of lamb1 from mutants revealed a non-sense mutation. These results identify a role for Laminin αl and Laminin β1 in notochord differentiation. Concurrent work in our laboratory revealed that the third mutant, sly, encodes the Laminin γl chain (Parsons et al., 2002). Thus, the laminin 1 isoform, a heterotrimer comprising the α1β1γ1 chains, is necessary for notochord differentiation. bal mutants differ from gup and sly, as failure of notochord differentiation is not as extensive, occurring only in anterior regions. We hypothesised this was due to a redundant role of another a chain. Characterisation of lama4 and lama5, encoding Laminin α4 and α5 chains, respectively, showed that both control aspects of notochord differentiation. Furthermore, lama5 has a functionally redundant role with lama1 during CNS development. Characterisation of lama2 identifies a role for Laminin α2 chain in muscle function, consistent with loss-of-function phenotypes in human and mouse. Hence, I demonstrate different roles for specific laminin chains during zebrafish development, confirming and extending results from studies in other vertebrate systems. Finally, I studied integrin α6, integrin β4, and integrin-linked kinase (ILK), to determine their role during development. The results suggest these genes control cell movements during gastrulation, rather than notochord differentiation.

Published
2002

19. A novel ILK/STAT3 pathway controls plasticity in a neural stem cell model of glioblastoma

Author

Loftus, Alexander E. P., Romano, Marianna S., Phuong, Anh Nguyen, Muir, Morwenna T., Dawson, John C., Avalle, Lidia, Douglas, Adam T., Mort, Richard L., Byron, Adam, Carragher, Neil O., Pollard, Steven M., Brunton, Valerie G., Frame, Margaret C., Loftus, Alexander E. P., Romano, Marianna S., Phuong, Anh Nguyen, Muir, Morwenna T., Dawson, John C., Avalle, Lidia, Douglas, Adam T., Mort, Richard L., Byron, Adam, Carragher, Neil O., Pollard, Steven M., Brunton, Valerie G., and Frame, Margaret C.

Published
2023

20. Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells

Author

Toledo, Chad M., Ding, Yu, Hoellerbauer, Pia, Davis, Ryan J., Basom, Ryan, Girard, Emily J., Lee, Eunjee, Corrin, Philip, Hart, Traver, Bolouri, Hamid, Davison, Jerry, Zhang, Qing, Hardcastle, Justin, Aronow, Bruce J., Plaisier, Christopher L., Baliga, Nitin S., Moffat, Jason, Lin, Qi, Li, Xiao-Nan, Nam, Do-Hyun, Lee, Jeongwu, Pollard, Steven M., Zhu, Jun, Delrow, Jeffery J., Clurman, Bruce E., Olson, James M., and Paddison, Patrick J.

Published
2015
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22. Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering in glioblastoma stem cells

Author

Purshouse, Karin, primary, Friman, Elias T, additional, Boyle, Shelagh, additional, Dewari, Pooran Singh, additional, Grant, Vivien, additional, Hamdan, Alhafidz, additional, Morrison, Gillian M, additional, Brennan, Paul M, additional, Beentjes, Sjoerd V, additional, Pollard, Steven M, additional, and Bickmore, Wendy A, additional

Published
2022
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26. High expression of MKP1/DUSP1 counteracts glioma stem cell activity and mediates HDAC inhibitor response

Author

Arrizabalaga, Olatz, Moreno-Cugnon, Leire, Auzmendi-Iriarte, Jaione, Aldaz, Paula, Ibanez de Caceres, Inmaculada, Garros-Regulez, Laura, Moncho-Amor, Veronica, Torres-Bayona, Sergio, Pernía, Olga, Pintado-Berninches, Laura, Carrasco-Ramirez, Patricia, Cortes-Sempere, María, Rosas, Rocío, Sanchez-Gomez, Pilar, Ruiz, Irune, Caren, Helena, Pollard, Steven, Garcia, Idoia, Sacido, Angel-Ayuso, Lovell-Badge, Robin, Belda-Iniesta, Cristobal, Sampron, Nicolas, Perona, Rosario, and Matheu, Ander

Published
2017
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27. High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML

Author

Bioquímica y biología molecular, Biokimika eta biologia molekularra, Aldaz Donamaría, Paula, Martín Martín, Natalia, Sáenz Antoñanzas, Ander, Carrasco-Garcia, Estefania, Álvarez-Satta, María, Elúa Pinin, Alejandro, Pollard, Steven M., Lawrie, Charles H., Moreno-Valladares, Manuel, Samprón Lebed, Nicolás, Hench, Jürgen, Lovell-Badge, Robin, Carracedo Pérez, Arkaitz, Matheu Fernández, Ander, Bioquímica y biología molecular, Biokimika eta biologia molekularra, Aldaz Donamaría, Paula, Martín Martín, Natalia, Sáenz Antoñanzas, Ander, Carrasco-Garcia, Estefania, Álvarez-Satta, María, Elúa Pinin, Alejandro, Pollard, Steven M., Lawrie, Charles H., Moreno-Valladares, Manuel, Samprón Lebed, Nicolás, Hench, Jürgen, Lovell-Badge, Robin, Carracedo Pérez, Arkaitz, and Matheu Fernández, Ander

Abstract

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade.

Published
2022

28. From cohorts to molecules : Adverse impacts of endocrine disrupting mixtures

Author

Caporale, Nicolo, Leemans, Michelle, Birgersson, Lina, Germain, Pierre-Luc, Cheroni, Cristina, Borbely, Gabor, Engdahl, Elin, Lindh, Christian, Bressan, Raul Bardini, Cavallo, Francesca, Chorev, Nadav Even, D'Agostino, Giuseppe Alessandro, Pollard, Steven M., Rigoli, Marco Tullio, Tenderini, Erika, Tobon, Alejandro Lopez, Trattaro, Sebastiano, Troglio, Flavia, Zanella, Matteo, Bergman, Ake, Damdimopoulou, Pauliina, Jönsson, Maria, Kiess, Wieland, Kitraki, Efthymia, Kiviranta, Hannu, Nanberg, Eewa, Oberg, Mattias, Rantakokko, Panu, Ruden, Christina, Soder, Olle, Bornehag, Carl-Gustaf, Demeneix, Barbara, Fini, Jean-Baptiste, Gennings, Chris, Rüegg, Joëlle, Sturve, Joachim, Testa, Giuseppe, Caporale, Nicolo, Leemans, Michelle, Birgersson, Lina, Germain, Pierre-Luc, Cheroni, Cristina, Borbely, Gabor, Engdahl, Elin, Lindh, Christian, Bressan, Raul Bardini, Cavallo, Francesca, Chorev, Nadav Even, D'Agostino, Giuseppe Alessandro, Pollard, Steven M., Rigoli, Marco Tullio, Tenderini, Erika, Tobon, Alejandro Lopez, Trattaro, Sebastiano, Troglio, Flavia, Zanella, Matteo, Bergman, Ake, Damdimopoulou, Pauliina, Jönsson, Maria, Kiess, Wieland, Kitraki, Efthymia, Kiviranta, Hannu, Nanberg, Eewa, Oberg, Mattias, Rantakokko, Panu, Ruden, Christina, Soder, Olle, Bornehag, Carl-Gustaf, Demeneix, Barbara, Fini, Jean-Baptiste, Gennings, Chris, Rüegg, Joëlle, Sturve, Joachim, and Testa, Giuseppe

Abstract

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Published
2022
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29. High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML

Author

Aldaz, Paula, primary, Martín-Martín, Natalia, additional, Saenz-Antoñanzas, Ander, additional, Carrasco-Garcia, Estefania, additional, Álvarez-Satta, María, additional, Elúa-Pinin, Alejandro, additional, Pollard, Steven M., additional, Lawrie, Charles H., additional, Moreno-Valladares, Manuel, additional, Samprón, Nicolás, additional, Hench, Jürgen, additional, Lovell-Badge, Robin, additional, Carracedo, Arkaitz, additional, and Matheu, Ander, additional

Published
2022
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34. Nanog promotes transfer of pluripotency after cell fusion

Author

Silva, Jose, Chambers, Ian, Pollard, Steven, and Smith, Austin

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Jose Silva [1]; Ian Chambers [1]; Steven Pollard [1]; Austin Smith (corresponding author) [1, 2] Through cell fusion, embryonic stem (ES) cells can erase the developmental programming of differentiated [...]

Published
2006
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35. Essential and overlapping roles for laminin alpha chains in notochord and blood vessel formation

Author

Pollard, Steven M., Parsons, Michael J., Kamei, Makoto, Kettleborough, Ross N.W., Thomas, Kevin A., Pham, Van N., Bae, Moon-Kyoung, Scott, Annabelle, Weinstein, Brant M., and Stemple, Derek L.

Subjects
Blood vessels -- Growth, Laminin -- Research, Notochord -- Growth, Zebra fish -- Research, Embryology, Experimental, Company growth, Biological sciences
Abstract

The contribution of laminin alpha chains in the development of the notochord and blood vessels in the embryos of zebra fish is studied.

Published
2006

44. Neural G0: a quiescent‐like state found in neuroepithelial‐derived cells and glioma.

Author

O'Connor, Samantha A, Feldman, Heather M, Arora, Sonali, Hoellerbauer, Pia, Toledo, Chad M, Corrin, Philip, Carter, Lucas, Kufeld, Megan, Bolouri, Hamid, Basom, Ryan, Delrow, Jeffrey, McFaline‐Figueroa, José L, Trapnell, Cole, Pollard, Steven M, Patel, Anoop, Paddison, Patrick J, and Plaisier, Christopher L

Subjects
NEURAL stem cells, HUMAN stem cells, GLIOMAS, HUMAN cell cycle, CELL cycle, CELL cycle regulation
Abstract

Single‐cell RNA sequencing has emerged as a powerful tool for resolving cellular states associated with normal and maligned developmental processes. Here, we used scRNA‐seq to examine the cell cycle states of expanding human neural stem cells (hNSCs). From these data, we constructed a cell cycle classifier that identifies traditional cell cycle phases and a putative quiescent‐like state in neuroepithelial‐derived cell types during mammalian neurogenesis and in gliomas. The Neural G0 markers are enriched with quiescent NSC genes and other neurodevelopmental markers found in non‐dividing neural progenitors. Putative glioblastoma stem‐like cells were significantly enriched in the Neural G0 cell population. Neural G0 cell populations and gene expression are significantly associated with less aggressive tumors and extended patient survival for gliomas. Genetic screens to identify modulators of Neural G0 revealed that knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down‐regulation of quiescence‐associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 represents a dynamic quiescent‐like state found in neuroepithelial‐derived cells and gliomas. SYNOPSIS: scRNA‐seq and functional genomics are applied to human neural stem cells to characterize cell cycle phases and factors increasing proliferative rate. A new cell cycle state "Neural G0" is discovered, offering insights into glioma patient tumors and patient survival. Unsupervised cell clustering reveals eight distinct cell cycle phases in human neural stem cells.A novel Neural G0 cell cycle phase is characterized by up‐regulation of genes with key roles in neural development.Increased expression of a GBM‐specific Neural G0 gene signature is associated with better prognosis for glioma patients, independent of tumor grade and IDH1/2 mutation.A functional‐genomics screen identifies genes that alter the time spent in G0/G1‐like states thereby increasing the proliferative rate of neural stem cells. [ABSTRACT FROM AUTHOR]

Published
2021
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45. Pediatric brain tumor cells release exosomes with a miRNA repertoire that differs from exosomes secreted by normal cells

Author

Tűzesi, Ágota, Kling, Teresia, Wenger, Anna, Lunavat, Taral R., Jang, Su Chul, Rydenhag, Bertil, Lötvall, Jan, Pollard, Steven M., Danielsson, Anna, and Carén, Helena

Subjects
cancer stem cells, pediatric, microRNA, glioma, Journal Article, exosomes, Research Paper
Abstract

High-grade gliomas (HGGs) are very aggressive brain tumors with a cancer stem cell component. Cells, including cancer stem cells, release vesicles called exosomes which contain small non-coding RNAs such as microRNAs (miRNAs). These are thought to play an important role in cell-cell communication. However, we have limited knowledge of the types of exosomal miRNAs released by pediatric HGG stem cells; a prerequisite for exploring their potential roles in HGG biology. Here we isolated exosomes released by pediatric glioma stem cells (GSCs) and compared their repertoire of miRNAs to genetically normal neural stem cells (NSCs) exosomes, as well as their respective cellular miRNA content. Whereas cellular miRNAs are similar, we find that the exosomal miRNA profiles differ between normal and tumor cells, and identify several differentially expressed miRNAs. Of particular interest is miR-1290 and miR-1246, which have previously been linked to 'stemness' and invasion in other cancers. We demonstrate that GSC-secreted exosomes influence the gene expression of receiving NSCs, particularly targeting genes with a role in cell fate and tumorigenesis. Thus, our study shows that GSCs and NSCs have similar cellular miRNA profiles, yet differ significantly in the repertoire of exosomal miRNAs and these could influence malignant features of HGG.

Published
2017
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46. The transcription factor Foxg1 promotes optic fissure closure in the mouse by suppressing Wnt8b in the nasal optic stalk

Author

Smith, Rowena, Huang, Yu-Ting, Tian, Tian, Vojtasova, Dominika, Mesalles-Naranjo, Oscar, Pollard, Steven M., Pratt, Thomas, Price, David J., and Fotaki, Vassiliki

Subjects
Male, Mice, Knockout, genetic structures, optic cup, Development/Plasticity/Repair, Optic Disk, Forkhead Transcription Factors, Nerve Tissue Proteins, Foxg1, eye diseases, body regions, Coloboma, Mice, Inbred C57BL, Wnt Proteins, Mice, Pregnancy, Wnt8b, Mice, Inbred CBA, Animals, Female, sense organs, Research Articles, mouse, optic fissure, Transcription Factors
Abstract

During vertebrate eye morphogenesis, a transient fissure forms at its inferior part, known as the optic fissure. This will gradually close, giving rise to a healthy, spherical optic cup. Failure of the optic fissure to close gives rise to an ocular disorder known as coloboma. During this developmental process, Foxg1 is expressed in the optic neuroepithelium, with highest levels of expression in the nasal optic stalk. Foxg1−/− mutant mice have microphthalmic eyes with a large ventral coloboma. We found Wnt8b expression upregulated in the Foxg1−/− optic stalk and hypothesized that, similar to what is observed in telencephalic development, Foxg1 directs development of the optic neuroepithelium through transcriptional suppression of Wnt8b. To test this, we generated Foxg1−/−;Wnt8b−/− double mutants of either sex and found that the morphology of the optic cup and stalk and the closure of the optic fissure were substantially rescued in these embryos. This rescue correlates with restored Pax2 expression in the anterior tip of the optic fissure. In addition, although we do not find evidence implicating altered proliferation in the rescue, we observe a significant increase in apoptotic cell density in Foxg1−/−;Wnt8b−/− double mutants compared with the Foxg1−/− single mutant. Upregulation of Wnt/β-catenin target molecules in the optic cup and stalk may underlie the molecular and morphological defects in the Foxg1−/− mutant. Our results show that proper optic fissure closure relies on Wnt8b suppression by Foxg1 in the nasal optic stalk to maintain balanced apoptosis and Pax2 expression in the nasal and temporal edges of the fissure. SIGNIFICANCE STATEMENT Coloboma is an ocular disorder that may result in a loss of visual acuity and accounts for ∼10% of childhood blindness. It results from errors in the sealing of the optic fissure (OF), a transient structure at the bottom of the eye. Here, we investigate the colobomatous phenotype of the Foxg1−/− mutant mouse. We identify upregulated expression of Wnt8b in the optic stalk of Foxg1−/− mutants before OF closure initiates. Foxg1−/−;Wnt8b−/− double mutants show a substantial rescue of the Foxg1−/− coloboma phenotype, which correlates with a rescue in molecular and cellular defects of Foxg1−/− mutants. Our results unravel a new role of Foxg1 in promoting OF closure providing additional knowledge about the molecules and cellular mechanisms underlying coloboma formation.

Published
2017
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47. Differentiation therapy in glioma - screening for modulators of differentiation commitment

Author

Bulstrode, Harry and Pollard, Steven

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Objectives: It is now clear that neural stem cell identity in a subset of tumour cells is key to malignancy in high grade glioma, and probably also in lower grade lesions. Inducing stable therapeutic differentiation commitment in the glioma NS cells which persist after surgical resection offers the [for full text, please go to the a.m. URL], 68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS)

Published
2017
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48. Polymeric glabrescione B nanocapsules for passive targeting of Hedgehog-dependent tumor therapy

Author

Ingallina, Cinzia, Costa, Pedro M., Ghirga, Francesca, Klippstein, Rebecca, Wang, Julie T., Berardozzi, Simone, Hodgins, Naomi, Infante, Paola, Pollard, Steven M., Botta, Bruno, and Al-Jamal, Khuloud T.

Subjects
glabrescione B (GlaB), Hedgehog (Hh) pathway, oil-cored polymeric nanocapsules
Abstract

Aim: With the purpose of delivering high doses of glabrescione B (GlaB) to solid tumors after systemic administration, long-circulating GlaB-loaded oil-cored polymeric nanocapsules (NC-GlaB) were formulated. Materials & methods: Synthesis of GlaB and its encapsulation in nanocapsules (NCs) was performed. Empty and GlaB-loaded NCs were assessed for their physico-chemical properties, in vitro cytotoxicity and in vivo biodistribution. Results: GlaB was efficiently loaded into NCs (90%), which were small (160 nm), homogeneous and stable upon storage. Further, GlaB and NC-GlaB demonstrated specific activities against the cancer stem cells. Preliminary studies in tumor-bearing mice supported the ability of NC to accumulate in pancreatic tumors. Conclusion: This study provides early evidence that NC-GlaB has the potential to be utilized in a preclinical setting and justifies the need to perform therapeutic experiments in mice.

Published
2017
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49. Reprogramming cancer cells to pluripotency

Author

Stricker, Stefan and Pollard, Steven

Subjects
DNA methylation, epigenetics, Brain Neoplasms, Carcinogenesis, Induced Pluripotent Stem Cells, glioblastoma, reprogramming, Cellular Reprogramming, Epigenesis, Genetic, neural stem cell, iPS cells, Neural Stem Cells, Cell Line, Tumor, Neoplastic Stem Cells, cancer, Animals, Humans, Cell Lineage, Point of View, polycomb, Metabolic Networks and Pathways
Abstract

The epigenetic marks displayed by a cancer cell originate from two separate processes: The most prominent epigenetic signatures are associated with the cell of origin, i.e., the lineage and cell type identity imposed during development. The second set comprises those aberrant cancer-specific epigenetic marks that appear during tumor initiation or subsequent malignant progression. These are generally thought to associate with tumor-promoting pathways. As biochemical pathways regulating epigenetic mechanisms are potentially "druggable" and reversible, there is considerable interest in defining their roles in tumor genesis and growth, as they may represent therapeutic targets for treatment of human neoplasias. (1) However, despite the potential importance of epigenetic modifications in human cancer, it has been difficult to determine when, where and how epigenetic disruptions occur, and if they have important functional roles in sustaining the malignant state.

Published
2014

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