![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
Senior Lecturer, Deputy Director European Cancer Stem Cell Research Institute
School of Biosciences
- fas@cardiff.ac.uk
- +44 29206 88500
- Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
- Available for postgraduate supervision
Overview
Research overview
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.
Publication
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)
Research
Summary
My lab investigates how stemness and cell differentiation are regulated in brain cancer and CNS homeostasis.
Brain Cancer Stem Cells
Brain cancers, especially glioblastoma, continue to carry an exceedingly poor prognosis despite several decades of research directed at improving our understanding and management of these diseases. The cancer stem cell hypothesis has helped to shift the scientific focus towards the study of specific tumour cell types, but the actual functions of individual cancer cell subpopulations within a single tumour are poorly understood. However, it is becoming increasingly clear that some cancer cells are more capable of inducing tumour growth and more resistant to conventional therapies. We call these cancer stem cells. Whether cancer stem cells are the source of functionally discreet tumour cell subpopulations remains unknown.
Stem-cell Transcription Factors
My research focuses on regulatory mechanisms that govern essential processes of malignancy in glioblastoma cancer stem cells (GSCs), such as tissue invasion, therapy resistance and the initiation of tumour growth. The transcription factor ZEB1 (zinc finger E-box binding homeobox 1) is able to regulate all of these processes in GSCs (Siebzehnrubl et al. 2013; Hoang-Minh et al. 2018) through an intricate pattern of regulatory steps involving microRNAs and downstream transcription factors and effector genes. ZEB1 is part of an auto-regulatory loop together with SOX2 and OLIG2, two additional stem cell transcription factors, that can drive tumour growth in glioblastoma. My lab investigates whether the transcription factor ZEB1 is a molecular regulator of cell state transition in GSCs.
Functions of ZEB1 in GSCs
In addition to their greater potential for initiating tumour growth and recurrence, GSCs are highly invasive and resistant to chemo- and radiotherapy. We have found that higher expression of ZEB1 in GSCs compared to non-stem glioblastoma cells causes increased expression of the chemoresistance enzyme, MGMT. ZEB1 further promotes GSC invasion through upregulation of the axon guidance molecule, ROBO1 (Fig. 1). Therefore, ZEB1 is a key regulator of multiple pro-malignant processes in GSCs.
Environmental regulators of ZEB1
The protein structure of transcription factors is usually very flexible, as these proteins interact with a number of potential binding partners and DNA to exert their regulatory functions. Because of this, transcription factors lack classical binding pockets that are present in many enzymes and present challenging targets for pharmacological inhibition.
We are therefore identifying upstream regulators of ZEB1 expression that are present in the tumour microenvironment and that may present better opportunities for pharmacological targeting.
Functions of ZEB1 in the normal brain
ZEB1 is known as a transcriptional regulator in cancer stem cells, while its functions in normal tissues are less understood. Constitutive knockout of ZEB1 is lethal around birth, therefore studies on the functions of ZEB1 in the CNS have thus far been limited to embryonic development.
We are currently investigating the functions of ZEB1 in astrocytes, and in homeostasis of the adult brain using new conditionally inducible transgenic models.
Current grant support
As lead applicant
MRC “Proteostatic regulation of glioblastoma stemness” (2023 – 2027, FEC £1.6m)
As co-applicant
BBSRC SWBio DTP “How are astrocytes made? Transcriptional regulation of astrocyte specification across development and adulthood” (2022-2026, £70k)
External collaborators
Karin Forsberg-Nilsson (Uppsala University, Sweden)
Justin D. Lathia (Cleveland Clinic, USA)
Thomas Brabletz (University Erlangen-Nuremberg, Germany)
Geert Berx (VIB Ghent, Belgium)
Affiliated Staff
- Dr Suresh Kushik
- Mrs Dorit Siebzehnruebl
Postgraduate Research Students
- Ms Ayesha Begum
- Ms Niharika Singh
Biography
Florian A Siebzehnrubl is a Senior Lecturer within the School of Biosciences at Cardiff University and a Deputy Director of the European Cancer Stem Cell Research Institute. He received his PhD from the Friedrich-Alexander University Erlangen-Nuremberg in 2007. He then trained with Prof Dennis Steindler and Prof Brent Reynolds at the University of Florida, two pioneers in the field of brain cancer stem cell research. In 2014 he moved to Cardiff where he is leading the Astroglia Cell Biology Group. He has a track record of >15 years in adult neural stem cells and cancer stem cell research, using human tissue culture systems and animal models to study how stemness and cell differentiation are regulated in CNS homeostasis, neurodegenerative diseases and brain cancer. He is an expert in astroglia and stem cell biology and molecular regulators of stemness. His group have reported on metabolic differences between glioblastoma stem and non-stem cells, changes in stem cell activity and neuronal differentiation in Huntington’s disease, and most recently on signalling pathways that regulate cancer stemness in glioblastoma. Dr Siebzehnrubl’s group is funded by the MRC, Innovate UK, NC3Rs, and Tenovus Cancer Care.
Supervisions
Research in my lab revolves around the themes listed below. If this is of interest to you, please contact me so we can generate a project outline together.
- Brain cancer stem cells
- Therapeutics for brain cancer
- FGF signaling
- Adult neurogenesis
- Neural stem cells
- Astrocyte biology
- Brain injury
Research themes
Specialisms
- Stem cells
- Cancer cell biology
- Signal transduction
- Genomics and transcriptomics
