![Florian Siebzehnrubl BSc, MSc, PhD, FHEA](https://profiles-cardiff.imgix.net/attachments/1219?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Dr Florian Siebzehnrubl
BSc, MSc, PhD, FHEA
Uwch Ddarlithydd, Dirprwy Gyfarwyddwr Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop
Ysgol y Biowyddorau
- fas@caerdydd.ac.uk
- +44 29206 88500
- Adeilad Hadyn Ellis, Heol Maendy, Caerdydd, CF24 4HQ
- Ar gael fel goruchwyliwr ôl-raddedig
Trosolwyg
Stem cells exhibit remarkable abilities to maintain their identity and to generate cells of different lineages. In normal tissues, they are responsible for replacement of cells lost through wear and tear, and for tissue repair after injury. In cancer, neoplastic stem-like cells apparently have a greater capacity for initiating tumour growth and are frequently resistant to anti-cancer treatments.
My lab focuses on understanding the molecular regulators of normal and cancerous stem cells in the CNS. We use in vitro and in vivo approaches to address how neural stem cells maintain their identity in the brain, and how cancer stem cells contribute to malignancy and tumour progression in glioblastoma, the most common and most lethal brain cancer in adults.
Cyhoeddiad
2023
- Alshahrany, N., Begum, A., Siebzehnrubl, D., Jimenez-Pascual, A. and Siebzehnrubl, F. A. 2023. Spatial distribution and functional relevance of FGFR1 and FGFR2 expression for glioblastoma tumor invasion. Cancer Letters 571, article number: 216349. (10.1016/j.canlet.2023.216349)
- Singh, N., Siebzehnrubl, F. A. and Martinez Garay, I. 2023. Transcriptional control of embryonic and adult neural progenitor activity. Frontiers in Neuroscience 17, article number: 1217596. (10.3389/fnins.2023.1217596)
- Bates, E. A., Lovatt, C., Plein, A. R., Davies, J. A., Siebzehnrubl, F. A. and Parker, A. L. 2023. Engineering adenoviral vectors with improved GBM selectivity. Viruses 15(5), article number: 1086. (10.3390/v15051086)
- Brown, J. et al. 2023. A high-density 3-dimensional culture model of human glioblastoma for rapid screening of therapeutic resistance. Biochemical Pharmacology 208, article number: 115410. (10.1016/j.bcp.2023.115410)
2022
- Petrik, D., Jorgensen, S., Eftychidis, V. and Siebzehnrubl, F. A. 2022. Singular adult neural stem cells do not exist. Cells 11(4), article number: 722. (10.3390/cells11040722)
- Siebzehnrubl, F. A. 2022. Isolating and culturing of precursor cells from the adult human brain. In: Deleyrolle, L. P. ed. Neural Progenitor Cells: Methods and Protocols., Vol. 2389. Methods in Molecular Biology New York, NY: Springer, pp. 95-102., (10.1007/978-1-0716-1783-0_9)
2021
- Gupta, B. et al. 2021. The transcription factor ZEB1 regulates stem cell self-renewal and cell fate in the adult hippocampus. Cell Reports 36(8), article number: 109588. (10.1016/j.celrep.2021.109588)
- Pope, I. et al. 2021. Identifying subpopulations in multicellular systems by quantitative chemical imaging using label-free hyperspectral CARS microscopy. Analyst 146(7), pp. 2277-2291. (10.1039/D0AN02381G)
- Almotiri, A. et al. 2021. Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia. Journal of Clinical Investigation 131(1), article number: e129115. (10.1172/JCI129115)
2020
- Badr, C. E., Silver, D. J., Siebzehnrubl, F. A. and Deleyrolle, L. P. 2020. Metabolic heterogeneity and adaptability in brain tumors. Cellular and Molecular Life Sciences 77, pp. 5101-5119. (10.1007/s00018-020-03569-w)
- Scholz, N., Kurian, K. M., Siebzehnrubl, F. A. and Licchesi, J. D. F. 2020. Targeting the ubiquitin system in glioblastoma. Frontiers in Oncology 10, article number: 574011. (10.3389/fonc.2020.574011)
- Jimenez-Pascual, A., Mitchell, K., Siebzehnrubl, F. A. and Lathia, J. D. 2020. FGF2: a novel druggable target for glioblastoma?. Expert Opinion on Therapeutic Targets 24(4), pp. 311-318. (10.1080/14728222.2020.1736558)
2019
- Jimenez-Pascual, A. et al. 2019. ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells. Cancer Discovery 9(11), pp. 1574-1589. (10.1158/2159-8290.CD-18-1308)
- Jimenez-Pascual, A., Lathia, J. D. and Siebzehnrubl, F. A. 2019. ADAMDEC1 and FGF2/FGFR1 signaling constitute a positive feedback loop to maintain GBM cancer stem cells. Molecular & Cellular Oncology 7(1), article number: 1684787. (10.1080/23723556.2019.1684787)
- Jimenez-Pascual, A. and Siebzehnrubl, F. A. 2019. Fibroblast growth factor receptor functions in glioblastoma. Cells 8(7), article number: 715. (10.3390/cells8070715)
2018
- Hoang-Minh, L. B. et al. 2018. Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma. EMBO Journal 37(23), article number: e98772. (10.15252/embj.201798772)
- Siebzehnrubl, F. A. et al. 2018. Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition. Proceedings of the National Academy of Sciences 115(37), pp. E8765-E8774. (10.1073/pnas.1807962115)
2017
- Roy, A. et al. 2017. Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression. Oncotarget 8, pp. 24815-24827. (10.18632/oncotarget.15820)
2015
- Kahlert, U. D. et al. 2015. ZEB1 promotes invasion in human fetal neural stem cells and hypoxic glioma neurospheres. Brain Pathology 25(6), pp. 724-732. (10.1111/bpa.12240)
- Siebzehnrubl, F. 2015. Application of an RNA amplification method for reliable single-cell transcriptome analysis. Biotechniques 59(3), pp. 137-148. (10.2144/000114331)
2014
- Vedam-Mai, V. et al. 2014. Increased precursor cell proliferation after deep brain stimulation for Parkinson's disease: a human study. PLoS ONE 9(3), article number: e88770. (10.1371/journal.pone.0088770)
- Sarkisian, M. R. et al. 2014. Detection of primary cilia in human glioblastoma. Journal of Neuro-Oncology 117(1), pp. 15-24. (10.1007/s11060-013-1340-y)
2013
- Silver, D. J. et al. 2013. Chondroitin Sulfate Proteoglycans Potently Inhibit Invasion and Serve as a Central Organizer of the Brain Tumor Microenvironment. Journal of Neuroscience 33(39), pp. 15603-15617. (10.1523/JNEUROSCI.3004-12.2013)
- Siebzehnrubl, F. et al. 2013. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Molecular Medicine 5(8), pp. 1196-1212. (10.1002/emmm.201302827)
- Siebzehnrubl, F. and Steindler, D. A. 2013. Isolating and culturing of precursor cells from the adult human brain. In: Reynolds, B. A. and Delerolle, L. P. eds. Neural Progenitor Cells., Vol. 1059. Methods in Molecular Biology Springer, pp. 79-86., (10.1007/978-1-62703-574-3_7)
2012
- Wang, S. et al. 2012. Neurogenic potential of progenitor cells isolated from postmortem human Parkinsonian brains. Brain Research 1464, pp. 61-72. (10.1016/j.brainres.2012.04.039)
2011
- Steffenhagen, C. et al. 2011. Identity, fate and potential of cells grown as neurospheres: species matters. Stem Cell Reviews and Reports 7(4), pp. 815-835. (10.1007/s12015-011-9251-9)
- Siebzehnrubl, F., Reynolds, B. A., Vescovi, A., Steindler, D. A. and Deleyrolle, L. P. 2011. The origins of glioma: E pluribus unum?. GLIA 59(8), pp. 1135-1147. (10.1002/glia.21143)
- Deleyrolle, L. P. et al. 2011. Evidence for label-retaining tumour-initiating cells in human glioblastoma. Brain 134, pp. 1331-1343. (10.1093/brain/awr081)
- Siebzehnrubl, F., Vedam-Mai, V., Azari, H., Reynolds, B. A. and Deleyrolle, L. P. 2011. Isolation and characterization of adult neural stem cells. In: Filippi, M. and Geiger, H. eds. Stem Cell Migration., Vol. 750. Methods in Molecular Biology Springer, pp. 61-77., (10.1007/978-1-61779-145-1_4)
2010
- Coras, R. et al. 2010. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain 133(11), pp. 3359-3372. (10.1093/brain/awq215)
2009
- Siebzehnrubl, F. et al. 2009. Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells. Brain Pathology 19(3), pp. 399-408. (10.1111/j.1750-3639.2008.00189.x)
- Weiss, S., Siebzehnrubl, F., Kreutzer, J., Bluemcke, I. and Buslei, R. 2009. Evidence for a progenitor cell population in the human pituitary. Clinical Neuropathology 28(4), pp. 309-318.
- Rivera, F. J. et al. 2009. Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cellular Physiology and Biochemistry 24(3-4), pp. 317-324. (10.1159/000233256)
2008
- Siebzehnrubl, F. and Blumcke, I. 2008. Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies. Epilepsia 49(s5), pp. 55-65. (10.1111/j.1528-1167.2008.01638.x)
- Huttner, H. B. et al. 2008. The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells 26(3), pp. 698-705. (10.1634/stemcells.2007-0639)
2007
- Coras, R. et al. 2007. The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion. Molecular Cancer Therapeutics 6(6), pp. 1745-1754. (10.1158/1535-7163.MCT-06-0763)
- Buslei, R. et al. 2007. Nuclear beta-catenin accumulation associates with epithelial morphogenesis in craniopharyngiomas. Acta Neuropathologica 113(5), pp. 585-590.
- Siebzehnrubl, F., Buslei, R., Eyupoglu, I. Y., Seufert, S., Hahnen, E. and Blumcke, I. 2007. Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells. Experimental Brain Research 176(4), pp. 672-678. (10.1007/s00221-006-0831-x)
2006
- Hoelsken, A. et al. 2006. Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. Acta Neuropathologica 112(2), pp. 205-215. (10.1007/s00401-006-0082-8)
- Hahnen, E. et al. 2006. In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. Journal of Neurochemistry 98(1), pp. 193-202. (10.1111/j.1471-4159.2006.03868.x)
- Buslei, R. et al. 2006. Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas. Acta Neuropathologica 111(3), pp. 264-271. (10.1007/s00401-005-0009-9)
- Eyupoglu, I. Y. et al. 2006. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Molecular Cancer Therapeutics 5(5), pp. 1248. (10.1158/1535-7163.MCT-05-0533)
2005
- Buslei, R. et al. 2005. Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathologica 109(6), pp. 589-597.
- Eyupoglu, I. Y. et al. 2005. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. Journal of Neurochemistry 93(4), pp. 992-999. (10.1111/j.1471-4159.2005.03098.x)
- Eyupoglu, I. Y., Hahnen, E., Heckel, A., Siebzehnrubl, F., Buslei, R., Fahlbusch, R. and Blumcke, I. 2005. Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note. Journal of Neurosurgery 102(4), pp. 738-744. (10.3171/jns.2005.102.4.0738)
Articles
- Alshahrany, N., Begum, A., Siebzehnrubl, D., Jimenez-Pascual, A. and Siebzehnrubl, F. A. 2023. Spatial distribution and functional relevance of FGFR1 and FGFR2 expression for glioblastoma tumor invasion. Cancer Letters 571, article number: 216349. (10.1016/j.canlet.2023.216349)
- Singh, N., Siebzehnrubl, F. A. and Martinez Garay, I. 2023. Transcriptional control of embryonic and adult neural progenitor activity. Frontiers in Neuroscience 17, article number: 1217596. (10.3389/fnins.2023.1217596)
- Bates, E. A., Lovatt, C., Plein, A. R., Davies, J. A., Siebzehnrubl, F. A. and Parker, A. L. 2023. Engineering adenoviral vectors with improved GBM selectivity. Viruses 15(5), article number: 1086. (10.3390/v15051086)
- Brown, J. et al. 2023. A high-density 3-dimensional culture model of human glioblastoma for rapid screening of therapeutic resistance. Biochemical Pharmacology 208, article number: 115410. (10.1016/j.bcp.2023.115410)
- Petrik, D., Jorgensen, S., Eftychidis, V. and Siebzehnrubl, F. A. 2022. Singular adult neural stem cells do not exist. Cells 11(4), article number: 722. (10.3390/cells11040722)
- Gupta, B. et al. 2021. The transcription factor ZEB1 regulates stem cell self-renewal and cell fate in the adult hippocampus. Cell Reports 36(8), article number: 109588. (10.1016/j.celrep.2021.109588)
- Pope, I. et al. 2021. Identifying subpopulations in multicellular systems by quantitative chemical imaging using label-free hyperspectral CARS microscopy. Analyst 146(7), pp. 2277-2291. (10.1039/D0AN02381G)
- Almotiri, A. et al. 2021. Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia. Journal of Clinical Investigation 131(1), article number: e129115. (10.1172/JCI129115)
- Badr, C. E., Silver, D. J., Siebzehnrubl, F. A. and Deleyrolle, L. P. 2020. Metabolic heterogeneity and adaptability in brain tumors. Cellular and Molecular Life Sciences 77, pp. 5101-5119. (10.1007/s00018-020-03569-w)
- Scholz, N., Kurian, K. M., Siebzehnrubl, F. A. and Licchesi, J. D. F. 2020. Targeting the ubiquitin system in glioblastoma. Frontiers in Oncology 10, article number: 574011. (10.3389/fonc.2020.574011)
- Jimenez-Pascual, A., Mitchell, K., Siebzehnrubl, F. A. and Lathia, J. D. 2020. FGF2: a novel druggable target for glioblastoma?. Expert Opinion on Therapeutic Targets 24(4), pp. 311-318. (10.1080/14728222.2020.1736558)
- Jimenez-Pascual, A. et al. 2019. ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells. Cancer Discovery 9(11), pp. 1574-1589. (10.1158/2159-8290.CD-18-1308)
- Jimenez-Pascual, A., Lathia, J. D. and Siebzehnrubl, F. A. 2019. ADAMDEC1 and FGF2/FGFR1 signaling constitute a positive feedback loop to maintain GBM cancer stem cells. Molecular & Cellular Oncology 7(1), article number: 1684787. (10.1080/23723556.2019.1684787)
- Jimenez-Pascual, A. and Siebzehnrubl, F. A. 2019. Fibroblast growth factor receptor functions in glioblastoma. Cells 8(7), article number: 715. (10.3390/cells8070715)
- Hoang-Minh, L. B. et al. 2018. Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma. EMBO Journal 37(23), article number: e98772. (10.15252/embj.201798772)
- Siebzehnrubl, F. A. et al. 2018. Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition. Proceedings of the National Academy of Sciences 115(37), pp. E8765-E8774. (10.1073/pnas.1807962115)
- Roy, A. et al. 2017. Serglycin as a potential biomarker for glioma: association of serglycin expression, extent of mast cell recruitment and glioblastoma progression. Oncotarget 8, pp. 24815-24827. (10.18632/oncotarget.15820)
- Kahlert, U. D. et al. 2015. ZEB1 promotes invasion in human fetal neural stem cells and hypoxic glioma neurospheres. Brain Pathology 25(6), pp. 724-732. (10.1111/bpa.12240)
- Siebzehnrubl, F. 2015. Application of an RNA amplification method for reliable single-cell transcriptome analysis. Biotechniques 59(3), pp. 137-148. (10.2144/000114331)
- Vedam-Mai, V. et al. 2014. Increased precursor cell proliferation after deep brain stimulation for Parkinson's disease: a human study. PLoS ONE 9(3), article number: e88770. (10.1371/journal.pone.0088770)
- Sarkisian, M. R. et al. 2014. Detection of primary cilia in human glioblastoma. Journal of Neuro-Oncology 117(1), pp. 15-24. (10.1007/s11060-013-1340-y)
- Silver, D. J. et al. 2013. Chondroitin Sulfate Proteoglycans Potently Inhibit Invasion and Serve as a Central Organizer of the Brain Tumor Microenvironment. Journal of Neuroscience 33(39), pp. 15603-15617. (10.1523/JNEUROSCI.3004-12.2013)
- Siebzehnrubl, F. et al. 2013. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Molecular Medicine 5(8), pp. 1196-1212. (10.1002/emmm.201302827)
- Wang, S. et al. 2012. Neurogenic potential of progenitor cells isolated from postmortem human Parkinsonian brains. Brain Research 1464, pp. 61-72. (10.1016/j.brainres.2012.04.039)
- Steffenhagen, C. et al. 2011. Identity, fate and potential of cells grown as neurospheres: species matters. Stem Cell Reviews and Reports 7(4), pp. 815-835. (10.1007/s12015-011-9251-9)
- Siebzehnrubl, F., Reynolds, B. A., Vescovi, A., Steindler, D. A. and Deleyrolle, L. P. 2011. The origins of glioma: E pluribus unum?. GLIA 59(8), pp. 1135-1147. (10.1002/glia.21143)
- Deleyrolle, L. P. et al. 2011. Evidence for label-retaining tumour-initiating cells in human glioblastoma. Brain 134, pp. 1331-1343. (10.1093/brain/awr081)
- Coras, R. et al. 2010. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain 133(11), pp. 3359-3372. (10.1093/brain/awq215)
- Siebzehnrubl, F. et al. 2009. Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells. Brain Pathology 19(3), pp. 399-408. (10.1111/j.1750-3639.2008.00189.x)
- Weiss, S., Siebzehnrubl, F., Kreutzer, J., Bluemcke, I. and Buslei, R. 2009. Evidence for a progenitor cell population in the human pituitary. Clinical Neuropathology 28(4), pp. 309-318.
- Rivera, F. J. et al. 2009. Mesenchymal stem cells promote oligodendroglial differentiation in hippocampal slice cultures. Cellular Physiology and Biochemistry 24(3-4), pp. 317-324. (10.1159/000233256)
- Siebzehnrubl, F. and Blumcke, I. 2008. Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies. Epilepsia 49(s5), pp. 55-65. (10.1111/j.1528-1167.2008.01638.x)
- Huttner, H. B. et al. 2008. The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells 26(3), pp. 698-705. (10.1634/stemcells.2007-0639)
- Coras, R. et al. 2007. The peroxisome proliferator-activated receptor-gamma agonist troglitazone inhibits transforming growth factor-beta-mediated glioma cell migration and brain invasion. Molecular Cancer Therapeutics 6(6), pp. 1745-1754. (10.1158/1535-7163.MCT-06-0763)
- Buslei, R. et al. 2007. Nuclear beta-catenin accumulation associates with epithelial morphogenesis in craniopharyngiomas. Acta Neuropathologica 113(5), pp. 585-590.
- Siebzehnrubl, F., Buslei, R., Eyupoglu, I. Y., Seufert, S., Hahnen, E. and Blumcke, I. 2007. Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells. Experimental Brain Research 176(4), pp. 672-678. (10.1007/s00221-006-0831-x)
- Hoelsken, A. et al. 2006. Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases. Acta Neuropathologica 112(2), pp. 205-215. (10.1007/s00401-006-0082-8)
- Hahnen, E. et al. 2006. In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. Journal of Neurochemistry 98(1), pp. 193-202. (10.1111/j.1471-4159.2006.03868.x)
- Buslei, R. et al. 2006. Abundant hypermethylation of SOCS-1 in clinically silent pituitary adenomas. Acta Neuropathologica 111(3), pp. 264-271. (10.1007/s00401-005-0009-9)
- Eyupoglu, I. Y. et al. 2006. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Molecular Cancer Therapeutics 5(5), pp. 1248. (10.1158/1535-7163.MCT-05-0533)
- Buslei, R. et al. 2005. Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathologica 109(6), pp. 589-597.
- Eyupoglu, I. Y. et al. 2005. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. Journal of Neurochemistry 93(4), pp. 992-999. (10.1111/j.1471-4159.2005.03098.x)
- Eyupoglu, I. Y., Hahnen, E., Heckel, A., Siebzehnrubl, F., Buslei, R., Fahlbusch, R. and Blumcke, I. 2005. Malignant glioma-induced neuronal cell death in an organotypic glioma invasion model. Technical note. Journal of Neurosurgery 102(4), pp. 738-744. (10.3171/jns.2005.102.4.0738)
Book sections
- Siebzehnrubl, F. A. 2022. Isolating and culturing of precursor cells from the adult human brain. In: Deleyrolle, L. P. ed. Neural Progenitor Cells: Methods and Protocols., Vol. 2389. Methods in Molecular Biology New York, NY: Springer, pp. 95-102., (10.1007/978-1-0716-1783-0_9)
- Siebzehnrubl, F. and Steindler, D. A. 2013. Isolating and culturing of precursor cells from the adult human brain. In: Reynolds, B. A. and Delerolle, L. P. eds. Neural Progenitor Cells., Vol. 1059. Methods in Molecular Biology Springer, pp. 79-86., (10.1007/978-1-62703-574-3_7)
- Siebzehnrubl, F., Vedam-Mai, V., Azari, H., Reynolds, B. A. and Deleyrolle, L. P. 2011. Isolation and characterization of adult neural stem cells. In: Filippi, M. and Geiger, H. eds. Stem Cell Migration., Vol. 750. Methods in Molecular Biology Springer, pp. 61-77., (10.1007/978-1-61779-145-1_4)
Ymchwil
Crynodeb
Mae fy labordy yn ymchwilio i sut mae stemness a gwahaniaethu celloedd yn cael eu rheoleiddio mewn canser yr ymennydd a homeostasis CNS.
Bôn-gelloedd Canser yr Ymennydd
Mae canserau'r ymennydd, yn enwedig glioblastoma, yn parhau i gario prognosis hynod wael er gwaethaf sawl degawd o ymchwil wedi'i anelu at wella ein dealltwriaeth a'n rheolaeth o'r clefydau hyn. Mae'r ddamcaniaeth bôn-gelloedd canser wedi helpu i symud y ffocws gwyddonol tuag at astudio mathau penodol o gelloedd tiwmor, ond ni ddeellir yn iawn swyddogaethau is-boblogaethau celloedd canser unigol o fewn tiwmor sengl. Fodd bynnag, mae'n dod yn fwyfwy amlwg bod rhai celloedd canser yn fwy abl i ysgogi twf tiwmor ac yn fwy gwrthsefyll therapïau confensiynol. Rydyn ni'n galw'r bôn-gelloedd canser hyn. Nid yw p'un a yw bôn-gelloedd canser yn ffynhonnell is-boblogaethau celloedd tiwmor synhwyrol swyddogaethol yn anhysbys o hyd.
Ffactorau Trawsgrifio bôn-gelloedd
Mae fy ymchwil yn canolbwyntio ar fecanweithiau rheoleiddio sy'n llywodraethu prosesau hanfodol malaen mewn bôn-gelloedd canser glioblastoma (GSCs), megis goresgyniad meinwe, ymwrthedd therapi a chychwyn twf tiwmor. Mae'r ffactor trawsgrifio ZEB1 (sinc-bys E-bocs rhwymo homeobox 1) yn gallu rheoleiddio'r holl brosesau hyn yn GSCs (Siebzehnrubl et al. 2013; Hoang-Minh et al. 2018) trwy batrwm cymhleth o gamau rheoleiddio sy'n cynnwys microRNAs a ffactorau trawsgrifio i lawr yr afon a genynnau effaithor. Mae ZEB1 yn rhan o ddolen awto-reoleiddiol ynghyd â SOX2 ac OLIG2, dau ffactor trawsgrifio bôn-gelloedd ychwanegol, a all yrru twf tiwmor mewn glioblastoma. Mae fy labordy yn ymchwilio a yw'r ffactor trawsgrifio ZEB1 yn rheoleiddiwr moleciwlaidd o drawsnewid cyflwr celloedd mewn GSCs.
Swyddogaethau ZEB1 yn GSCs
Yn ogystal â'u potensial mwy ar gyfer cychwyn twf tiwmor ac ailadrodd, mae GSCs yn ymledol iawn ac yn gallu gwrthsefyll chemo- a radiotherapi. Rydym wedi canfod bod mynegiant uwch o ZEB1 mewn GSCs o'i gymharu â chelloedd glioblastoma nad ydynt yn stemyn achosi mwy o fynegiant o'r ensym chemoresistance, MGMT. ZEB1 hyrwyddo ymosodiad GSC ymhellach trwy uwchreoleiddio'r moleciwl cyfarwyddyd axon, ROBO1 (Fig. 1). Felly, ZEB1 yn rheoleiddiwr allweddol o brosesau pro-malaen lluosog yn GSCs.
Rheoleiddwyr amgylcheddol ZEB1
Mae strwythur protein ffactorau trawsgrifio fel arfer yn hyblyg iawn, gan fod y proteinau hyn yn rhyngweithio â nifer o bartneriaid rhwymol posibl a DNA i weithredu eu swyddogaethau rheoleiddio. Oherwydd hyn, nid oes gan ffactorau trawsgrifio pocedi rhwymo clasurol sy'n bresennol mewn llawer o ensymau ac sy'n cyflwyno targedau heriol ar gyfer atal ffarmacolegol.
Felly, rydym yn nodi rheoleiddwyr i fyny'r afon o fynegiant ZEB1 sy'n bresennol yn y micro-amgylchedd tiwmor ac a allai gyflwyno gwell cyfleoedd ar gyfer targedu ffarmacolegol.
Swyddogaethau ZEB1 yn yr ymennydd arferol
Gelwir ZEB1 yn rheoleiddiwr trawsgrifio mewn bôn-gelloedd canser, tra bod ei swyddogaethau mewn meinweoedd arferol yn llai dealladwy. Mae sgil-effeithiau cyfansoddol o ZEB1 yn angheuol o amgylch genedigaeth, felly mae astudiaethau ar swyddogaethau ZEB1 yn y CNS hyd yma wedi'u cyfyngu i ddatblygiad embryonig.
Ar hyn o bryd rydym yn ymchwilio i swyddogaethau ZEB1 mewn astrocytes, ac yn homeostasis yr ymennydd oedolion gan ddefnyddio modelau trawsgenig newydd sy'n ysgogi'n amodol.
Cymorth grant cyfredol
Fel ymgeisydd arweiniol
MRC "Rheoleiddio proteostatig o stemness glioblastoma" (2023 – 2027, FEC £1.6m)
Fel cyd-ymgeisydd
BBSRC SWBio DTP "Sut mae astrocytes yn cael eu gwneud? Rheoleiddio trawsgrifio manyleb astrocyte ar draws datblygiad ac oedolaeth" (2022-2026, £70k)
Cydweithredwyr allanol
Karin Forsberg-Nilsson (Prifysgol Uppsala, Sweden)
Justin D. Lathia (Clinig Cleveland, UDA)
Thomas Brabletz (Prifysgol Erlangen-Nuremberg, yr Almaen)
Geert Berx (VIB Ghent, Gwlad Belg)
Staff Cysylltiedig
- Dr Suresh Kushik
- Mrs Dorit Siebzehnruebl
Myfyrwyr Ymchwil Ôl-raddedig
- Ms Ayesha Begum
- Ms Niharika Singh
Bywgraffiad
Mae Florian A Siebzehnrubl yn Uwch Ddarlithydd yn Ysgol y Biowyddorau ym Mhrifysgol Caerdydd ac yn Ddirprwy Gyfarwyddwr Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop. Derbyniodd ei PhD gan Brifysgol Friedrich-Alexander Erlangen-Nuremberg yn 2007. Yna hyfforddodd gyda'r Athro Dennis Steindler a'r Athro Brent Reynolds ym Mhrifysgol Florida, dau arloeswr ym maes ymchwil bôn-gelloedd canser yr ymennydd. Yn 2014 symudodd i Gaerdydd lle mae'n arwain Grŵp Bioleg Cell Astroglia. Mae ganddo hanes o >15 mlynedd mewn bôn-gelloedd nerfol oedolion ac ymchwil bôn-gelloedd canser, gan ddefnyddio systemau diwylliant meinwe dynol a modelau anifeiliaid i astudio sut mae stemness a gwahaniaethu celloedd yn cael eu rheoleiddio mewn homeostasis CNS, clefydau niwroddirywiol a chanser yr ymennydd. Mae'n arbenigwr mewn astroglia a bioleg bôn-gelloedd a rheoleiddwyr moleciwlaidd o stemness. Mae ei grŵp wedi adrodd ar wahaniaethau metabolaidd rhwng coesyn glioblastoma a chelloedd nad ydynt yn stemynau, newidiadau yng ngweithgarwch bôn-gelloedd a gwahaniaethu niwronau mewn clefyd Huntington, ac yn fwyaf diweddar ar lwybrau signalau sy'n rheoleiddio stemness canser mewn glioblastoma. Ariennir grŵp Dr Siebzehnrubl gan y MRC, Innovate UK, NC3Rs, a Gofal Canser Tenovus.
Meysydd goruchwyliaeth
- Brain cancer stem cells
- Anti-cancer therapeutics
- FGF signaling
- Adult neurogenesis
- Neural stem cells
- Astrocyte biology
- Brain injury
Themâu ymchwil
Arbenigeddau
- Celloedd bonyn
- Bioleg celloedd canser
- Transduction signal
- Genomeg a thrawsgrifiadau
