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4. Zeb1 modulates hematopoietic stem cell fates required for suppressing acute myeloid leukemia

Author

Almotiri, Alhomidi, Alzahrani, Hamed, Menendez-Gonzalez, Juan Bautista, Abdelfattah, Ali, Alotaibi, Badi, Saleh, Lubaid, Greene, Adelle, Georgiou, Mia, Gibbs, Alex, Alsayari, Amani, Taha, Sarab, Thomas, Leigh-anne, Shah, Dhruv, Edkins, Sarah, Giles, Peter, Stemmler, Marc P., Brabletz, Simone, Brabletz, Thomas, Boyd, Ashleigh S., Siebzehnrubl, Florian A., and Rodrigues, Neil P.

Subjects
Gene expression -- Health aspects, Stem cells -- Genetic aspects -- Health aspects, Cancer cells -- Genetic aspects -- Health aspects, Transcription factors -- Health aspects, Health care industry
Abstract

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal transition (EMT) transcription factor, confers properties of 'sternness,' such as self-renewal, in cancer. Yet little is known about the function of Zeb1 in adult stem cells. Here, we used the hematopoietic system as a well-established paradigm of stem cell biology to evaluate Zeb1-mediated regulation of adult stem cells. We employed a conditional genetic approach using the Mx1- Cre system to specifically knock out (KO) Zeb1 in adult hematopoietic stem cells (HSCs) and their downstream progeny. Acute genetic deletion of Zeb1 led to rapid-onset thymic atrophy and apoptosis-driven loss of thymocytes and T cells. A profound cell-autonomous self-renewal defect and multilineage differentiation block were observed in Zeb1-KO HSCs. Loss of Zeb1 in HSCs activated transcriptional programs of deregulated HSC maintenance and multilineage differentiation genes and of cell polarity consisting of cytoskeleton-, lipid metabolism/lipid membrane-, and cell adhesion-related genes. Notably, epithelial cell adhesion molecule (EpCAM) expression was prodigiously upregulated in Zeb1-KO HSCs, which correlated with enhanced cell survival, diminished mitochondrial metabolism, ribosome biogenesis, and differentiation capacity and an activated transcriptomic signature associated with acute myeloid leukemia (AML) signaling. ZEB1 expression was downregulated in AML patients, and Zeb1 KO in the malignant counterparts of HSCs--leukemic stem cells (LSCs)--accelerated MLL-AF9- and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Thus, Zeb1 acts as a transcriptional regulator in hematopoiesis, critically coordinating HSC self-renewal, apoptotic, and multilineage differentiation fates required to suppress leukemic potential in AML., Introduction Epithelial-mesenchymal transition (EMT) is a complex process that organizes specific changes in cellular fate and phenotype and is usually accompanied by loss of cell polarity and adhesion and increased [...]

Published
2021
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5. Low Proliferation and Differentiation Capacities of Adult Hippocampal Stem Cells Correlate with Memory Dysfunction in Humans

Author

Coras, Roland, Siebzehnrubl, Florian A., and Pauli, Elisabeth

Abstract

The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we assessed the neurogenic potential in the human hippocampal dentate gyrus by isolating adult human neural stem cells from 23 surgical "en bloc" hippocampus resections. After proliferation of the progenitor cell pool "in vitro" we identified two distinct patterns. Adult human neural stem cells with a high proliferation capacity were obtained in 11 patients. Most of the cells in the high proliferation capacity cultures were capable of neuronal differentiation (53 plus or minus 13% of "in vitro" cell population). A low proliferation capacity was observed in 12 specimens, and only few cells differentiated into neurons (4 plus or minus 2%). This was reflected by reduced numbers of proliferating cells "in vivo" as well as granule cells immunoreactive for doublecortin, brain-derived neurotrophic factor and cyclin-dependent kinase 5 in the low proliferation capacity group. High and low proliferation capacity groups differed dramatically in declarative memory tasks. Patients with high proliferation capacity stem cells had a normal memory performance prior to epilepsy surgery, while patients with low proliferation capacity stem cells showed severe learning and memory impairment. Histopathological examination revealed a highly significant correlation between granule cell loss in the dentate gyrus and the same patient's regenerative capacity "in vitro" (r = 0.813; P less than 0.001; linear regression: R[superscript 2][subscript adjusted] = 0.635), as well as the same patient's ability to store and recall new memories (r = 0.966; P = 0.001; linear regression: R[superscript 2][subscript adjusted] = 0.9). Our results suggest that encoding new memories is related to the regenerative capacity of the hippocampus in the human brain.

Published
2010
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10. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

Author

Siebzehnrubl, Florian A., Silver, Daniel J., Tugertimur, Bugra, Deleyrolle, Loic P., Siebzehnrubl, Dorit, Sarkisian, Matthew R., Devers, Kelly G., Yachnis, Antony T., Kupper, Marius D., Neal, Daniel, Nabilsi, Nancy H., Kladde, Michael P., Suslov, Oleg, Brabletz, Simone, Brabletz, Thomas, Reynolds, Brent A., and Steindler, Dennis A.

Published
2013
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14. STEM-07. THE ATYPICAL METALLOPROTEINASE ADAMDEC1 MAINTAINS A NOVEL FGF MEDIATED SIGNALLING NETWORK IN GLIOBLASTOMA CANCER STEM CELLS

Author

Jimenez-Pascual, Ana, primary, Hale, James, additional, Bayik, Defne, additional, Silver, Daniel, additional, Roversi, Gustavo, additional, Alban, Tyler, additional, McIntyre, Thomas, additional, Colombo, Giorgio, additional, Taraboletti, Giulia, additional, Holmberg, Karl, additional, Forsberg-Nilsson, Karin, additional, Lathia, Justin, additional, and Siebzehnrubl, Florian, additional

Published
2019
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16. The metalloproteinase ADAMDEC1 maintains a novel growth factor signalling loop in glioblastoma cancer stem cells

Author

Jimenez-Pascual, Ana, primary, Hale, James, additional, Kordowski, Anja, additional, Pugh, Jamie, additional, Rao, Shilpa, additional, Silver, Daniel, additional, Alban, Tyler, additional, Watson, Defne, additional, Chen, Rui, additional, McIntyre, Thomas, additional, Colombo, Giorgio, additional, Taraboletti, Giulia, additional, Holmberg, Karl, additional, Forsberg-Nilsson, Karin, additional, Lathia, Justin, additional, and Siebzehnrubl, Florian, additional

Published
2019
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21. Infiltrative and drug‐resistant slow‐cycling cells support metabolic heterogeneity in glioblastoma

Author

Hoang‐Minh, Lan B, primary, Siebzehnrubl, Florian A, additional, Yang, Changlin, additional, Suzuki‐Hatano, Silveli, additional, Dajac, Kyle, additional, Loche, Tyler, additional, Andrews, Nicholas, additional, Schmoll Massari, Michael, additional, Patel, Jaimin, additional, Amin, Krisha, additional, Vuong, Alvin, additional, Jimenez‐Pascual, Ana, additional, Kubilis, Paul, additional, Garrett, Timothy J, additional, Moneypenny, Craig, additional, Pacak, Christina A, additional, Huang, Jianping, additional, Sayour, Elias J, additional, Mitchell, Duane A, additional, Sarkisian, Matthew R, additional, Reynolds, Brent A, additional, and Deleyrolle, Loic P, additional

Published
2018
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22. Serglycin as a potential biomarker for glioma : association of serglycin expression, extent of mast cell recruitment and glioblastoma progression

Author

Roy, Ananya, Attarha, Sanaz, Weishaupt, Holger, Edqvist, Per-Henrik, Swartling, Fredrik J., Bergqvist, Michael, Siebzehnrubl, Florian, Smits, Anja, Pontén, Fredrik, and Tchougounova, Elena

Subjects
Cancer och onkologi, glioma, Cancer and Oncology, serglycin, ZEB1, CD44, mast cell
Abstract

Serglycin is an intracellular proteoglycan with a unique ability to adopt highly divergent structures by glycosylation with variable types of glycosaminoglycans (GAGs) when expressed by different cell types. Serglycin is overexpressed in aggressive cancers suggesting its protumorigenic role. In this study, we explored the expression of serglycin in human glioma and its correlation with survival and immune cell infiltration. We demonstrate that serglycin is expressed in glioma and that increased expression predicts poor survival of patients. Analysis of serglycin expression in a large cohort of low- and high-grade human glioma samples reveals that its expression is grade dependent and is positively correlated with mast cell (MC) infiltration. Moreover, serglycin expression in patient-derived glioma cells is significantly increased upon MC co-culture. This is also accompanied by increased expression of CXCL12, CXCL10, as well as markers of cancer progression, including CD44, ZEB1 and vimentin.\ud In conclusion, these findings indicate the importance of infiltrating MCs in glioma by modulating signaling cascades involving serglycin, CD44 and ZEB1. The present investigation reveals serglycin as a potential prognostic marker for glioma and demonstrates an association with the extent of MC recruitment and glioma progression, uncovering potential future therapeutic opportunities for patients.

Published
2017

23. STEM-09. TREATMENT-RESISTANT SLOW-CYCLING CELLS SUPPORT METABOLIC HETEROGENEITY AND ADAPTABILITY IN GLIOBLASTOMA

Author

Hoang-Minh, Lan, primary, Siebzehnrubl, Florian, additional, Yang, Changlin, additional, Dajac, Kyle, additional, Andrews, Nicholas, additional, Schmoll, Michael, additional, Amin, Krisha, additional, Vuong, Alvin, additional, Jimenez-Pascual, Ana, additional, Huang, Jianping, additional, Garrett, Timothy, additional, Sayour, Elias, additional, Mitchell, Duane, additional, Sarkisian, Matthew, additional, Reynolds, Brent A, additional, and Deleyrolle, Loic P, additional

Published
2017
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24. ADAMDEC1 and FGF2/FGFR1 signaling constitute a positive feedback loop to maintain GBM cancer stem cells.

Author

Jimenez-Pascual, Ana, Lathia, Justin D., and Siebzehnrubl, Florian A.

Subjects
CANCER stem cells, FIBROBLAST growth factor 2, METALLOPROTEINASES, FIBROBLAST growth factors, AUTOCRINE mechanisms
Abstract

Identification of targetable mechanisms that maintain glioblastoma cancer stem cells (CSCs) remain a priority. Our study reveals a new mechanism by which a disintegrin and metalloproteinase domain-like protein decysin 1 promotes CSC maintenance through the activation of a fibroblast growth factor autocrine signaling loop, which can be blocked pharmacologically. [ABSTRACT FROM AUTHOR]

Published
2020
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27. Increased Precursor Cell Proliferation after Deep Brain Stimulation for Parkinson's Disease: A Human Study

Author

Vedam-Mai, Vinata, primary, Gardner, Bronwen, additional, Okun, Michael S., additional, Siebzehnrubl, Florian A., additional, Kam, Monica, additional, Aponso, Palingu, additional, Steindler, Dennis A., additional, Yachnis, Anthony T., additional, Neal, Dan, additional, Oliver, Brittany U., additional, Rath, Sean J., additional, Faull, Richard L. M., additional, Reynolds, Brent A., additional, and Curtis, Maurice A., additional

Published
2014
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29. Abstract 4906: ZEB1 maintains self-renewal, invasion and chemoresistance of glioblastoma stem cells.

Author

Siebzehnrubl, Florian A., primary, Silver, Daniel J., additional, Tugertimur, Bugra, additional, Deleyrolle, Loic P., additional, Siebzehnrubl, Dorit, additional, Sarkisian, Matthew R., additional, Devers, Kelly G., additional, Yachnis, Antony T., additional, Kupper, Marius D., additional, Neal, Daniel, additional, Nabilsi, Nancy H., additional, Kladde, Michael P., additional, Suslov, Oleg, additional, Brabletz, Simone, additional, Brabletz, Thomas, additional, Reynolds, Brent A., additional, and Steindler, Dennis A., additional

Published
2013
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30. Abstract 1639: Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment.

Author

Silver, Daniel J., primary, Siebzehnrubl, Florian A., additional, Schildts, Michela J., additional, Yachnis, Anthony T., additional, Smith, George M., additional, Smith, Amy A., additional, Scheffler, Bjorn, additional, Reynolds, Brent A., additional, Silver, Jerry, additional, and Steindler, Dennis A., additional

Published
2013
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31. Abstract 4308: ZEB1 mediates invasion and chemoresistance of glioblastoma

Author

Siebzehnrubl, Florian, primary, Silver, Daniel, additional, Tugertimur, Bugra, additional, Deleyrolle, Loic, additional, Suslov, Oleg, additional, Siebzehnrubl, Dorit, additional, Sarkisian, Matthew, additional, Kuepper, Marius, additional, Yachnis, Antony, additional, Brabletz, Simone, additional, Brabletz, Thomas, additional, Reynolds, Brent, additional, and Steindler, Dennis, additional

Published
2012
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36. The Stem Cell Marker Prominin-1/CD133 on Membrane Particles in Human Cerebrospinal Fluid Offers Novel Approaches for Studying Central Nervous System Disease

Author

Huttner, Hagen B., primary, Janich, Peggy, additional, Köhrmann, Martin, additional, Jászai, József, additional, Siebzehnrubl, Florian, additional, Blümcke, Ingmar, additional, Suttorp, Meinolf, additional, Gahr, Manfred, additional, Kuhnt, Daniela, additional, Nimsky, Christopher, additional, Krex, Dietmar, additional, Schackert, Gabriele, additional, Löwenbrück, Kai, additional, Reichmann, Heinz, additional, Jüttler, Eric, additional, Hacke, Werner, additional, Schellinger, Peter D., additional, Schwab, Stefan, additional, Wilsch-Bräuninger, Michaela, additional, Marzesco, Anne-Marie, additional, and Corbeil, Denis, additional

Published
2007
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37. The Stem Cell Marker Prominin-1/CD133 on Membrane Particles in Human Cerebrospinal Fluid Offers Novel Approaches for Studying Central Nervous System Disease.

Author

Huttner, Hagen B., Janich, Peggy, Köhrmann, Martin, Jászai, József, Siebzehnrubl, Florian, Blümcke, Ingmar, Suttorp, Meinolf, Gahr, Manfred, Kuhnt, Daniela, Nimsky, Christopher, Krex, Dietmar, Schackert, Gabriele, Löwenbrück, Kai, Reichmann, Heinz, Jüttler, Eric, Hacke, Werner, Schellinger, Peter D., Schwab, Stefan, Wilsch-Bräuninger, Michaela, and Marzesco, Anne-Marie

Subjects
GLIOMAS, NERVOUS system tumors, NERVOUS system, HEMATOPOIETIC stem cells, BONE marrow cells
Abstract

Cerebrospinal fluid (CSF) is routinely used for diagnosing and monitoring neurological diseases. The CSF proteins used so far for diagnostic purposes (except for those associated with whole cells) are soluble. Here, we show that human CSF contains specific membrane particles that carry prominin- 1/CD133, a neural stem cell marker implicated in brain tumors, notably glioblastoma. Differential and equilibrium centrifugation and detergent solubility analyses showed that these membrane particles were similar in physical properties and microdomain organization to small membrane vesicles previously shown to be released from neural stem cells in the mouse embryo. The levels of membrane particle-associated prominin-1/CD133 declined during childhood and remained constant thereafter, with a remarkably narrow range in healthy adults. Glioblastoma patients showed elevated levels of membrane particle- associated prominin-1/CD133, which decreased dramatically in the final stage of the disease. Hence, analysis of CSF for membrane particles carrying the somatic stem cell marker prominin-1/CD133 offers a novel approach for studying human central nervous system disease. [ABSTRACT FROM AUTHOR]

Published
2008
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