The term neural stem cells refers to the progenitor cells that initiate lineages leading to the formation of differentiated neurons or glial cells. Neural stem cells are present in the developing brain and persist in restricted regions of postnatal and adult brains. During brain development the balance between neural stem cells proliferation and differentiation depends on a delicate interplay between several pathways. Interestingly, the same pathways are often deregulated in neurological disorders and brain cancer. One striking example of the tight link between development and oncogenesis is Medulloblastoma, the most prevalent malignant brain cancer in children. In the coming years, my research will focus on understanding the molecular and cellular mechanisms that regulates neural stem cells and neurons biology during brain cancer development and in neurological disorders.
Neurogenesis and stem cell biology
Despite neural stem cells have been widely studied in the past years, the mechanisms underlying their biology are still poorly understood. We are interested in studying how neural stem cells proliferate and differentiate during brain development. To this aim we will use cutting edge technology such as cellular lineage tracing, CRISPR/CAS9 and Next Generation Sequencing (NGS).
Medulloblastoma (MB) is the most common brain cancer affecting children and remains responsible for a high percentage of morbidity and mortality among cancer patients. During the past few years, studies on human MB and mouse models have uncovered the existence of four major MB groups: WNT, SHH, Group 3 and Group 4. SHH MB is caused by aberrant gain of function of the SHH pathway and develops in the cerebellum from granule neuron precursors (GNPs). Deciphering the link between normal development and oncogenesis will be of paramount importance for understanding the origins and mechanisms of brain tumorigenesis. In the coming years we will take advantage of different in vitro and in vivo genetically engineered models to study Medulloblastoma development
Human induced pluripotent stem cells (hiPSCs) as a model for brain disorders
Neuronal cells have been amongst the earliest cell types to be generated via efficient differentiation protocols from human induced pluripotent stem cells (hiPSCs). Differentiation of hiPSCs from healthy individuals into neuronal cells permits investigation and modelling of human neurodevelopmental processes. We will take advantage of this technology to produce hIPSCs from patients with brain disorders to characterize how brain neuronal stem cells and/or differentiated neurons are affected. Using hiPSCs will allow us to study how pathological processes drive abnormal human brain developmental and/or degenerative diseases.
- Luca Tiberi, PI
- Giuseppe Aiello, PostDoc
- Marica Anderle, PostDoc
- Francesco Antonica, PostDoc
- Claudio Ballabio, PostDoc
- Matteo Gianesello, Researcher
- Chiara Lago, PhD Student
- Lucia Santomaso, Researcher
2016, Armenise/Harvard Career Development Award.
2018, My First AIRC Grant.
2019, CARITRO Grant
Ballabio C, Anderle M, Gianesello M, Lago C, Miele E, Cardano M, Aiello G, Piazza S, Caron D, Gianno F, Ciolfi A, Pedace L, Matronuzzi A, Tartaglia M, Locatelli F, Ferretti E, Giangaspero F and Tiberi L*. Modeling Medulloblastoma in vivo and with human cerebellar organoids. Nature Communications. 2020 Feb. doi: 10.1038/s41467-019-13989-3.* Corresponding author
Aiello G, Ballabio C, Ruggeri R, Fagnocchi L, Anderle M, Morassut I, Caron D, Garilli F, Gianno F, Giangaspero F, Piazza S, Romanel A, Zippo A, Tiberi L*. Truncated-Brpf1 cooperates with Smoothened to induce adult Shh Medulloblastoma. Cell Rep. 2019 Dec 17;29(12):4036-4052.e10. doi: 10.1016/j.celrep.2019.11.046. *Corresponding author
Quan, X-J, L. Yuan, L. Tiberi, A. Claeys, N. De Geest, J. Yan, W. R. Xie, T. J. Klisch, R. van der Kant, J. Shymkowitz, Frederic Rousseau, M. Bollen, M. Beullens, H. Y. Zoghbi, P. Vanderhaeghen, B. A. Hassan. “Post-translational control of the temporal dynamics of transcription factor activity regulates neurogenesis”. Cell. 2016 Jan 28;164(3):460-75.
Tiberi L, Bonnefont J, van den Ameele J, Herpoel A, Bilheu A, Baron B, Vanderhaeghen P. “A BCL6/BCoR/Sirt1 complex Triggers Neurogenesis and Suppresses Medulloblastoma by Repressing Sonic Hedgehog Signalling.” Cancer Cell. 2014 Dec 8;26:797-812. FREE FEATURED ARTICLE
Rustighi A*, Zannini A*, Tiberi L, Piazza S, Sorrentino G, Sommaggio R, Rosato A, Santarpia L, Benvenuti F, Nuzzo S, Bicciato S, Aifantis I, Del Sal G. Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Molecular Medicine. 2014 Jan 1;6(1):99-119. * Equal contribution.
Dimidschstein J, Passante L, Dufour A, van den Ameele J, Tiberi L, Hrechdakian T, Adams R, Klein R, Chichung Lie D, Jossin Y, Vanderhaeghen P. Ephrin-B1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration. Neuron. 2013 Sep 18;79(6):1123-35.
Tiberi L*, van den Ameele J*, Dimidschstein J, Piccirilli J, Gall D, Herpoel A, Bilheu A, Bonnefont J, Iacovino M, Kyba M, Bouschet T, Vanderhaeghen P. BCL6 induces neurogenesis through Sirt1-dependent epigenetic repression of selective Notch transcriptional targets. Nature Neuroscience. 2012 Dec;15(12):1627-35.* Equal contribution.
van den Ameele J*, Tiberi L*, Bondue A*, Paulissen C, Herpoel A, Iacovino M, Kyba M, Blanpain C, Vanderhaeghen P. Eomesodermin induces Mesp1 expression and cardiac differentiation from embryonic stem cells in the absence of Activin. EMBO Reports. 2012 Apr;13(4):355-62. * Equal contribution.
Pietri S, Dimidschstein J, Tiberi L, Sotiropoulou PA, Bilheu A, Goffinet A, Achouri Y, Tissir F, Blanpain C, Jacquemin P, Vanderhaeghen P. Transcriptional Mechanisms of EphA7 Gene Expression in the Developing Cerebral Cortex. Cereb Cortex. 2012 Jul;22(7):1678-89.
Rustighi A*, Tiberi L*, Soldano A, Pece S, Nuciforo P, Capobianco A, Di Fiore P.P. and G. Del Sal. The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nature Cell Biology. 2009 Feb;11(2):133-42. * Equal contribution.
van den Ameele J*, Tiberi L*, Vanderhaeghen P and Espuny-Camacho I*. Thinking out of the dish: what to learn about cortical development using pluripotent stem cells. Trends in Neurosciences. 2014 Apr. 37(6):334-342. * Equal contribution.
Tiberi L, Vanderhaeghen P, van den Ameele J. Cortical neurogenesis and morphogens: diversity of cues, sources and functions. Current Opinion in Cell Biology. 2012 Apr;24(2):269-76.