Overview

NeuronsDefeating childhood and adult brain cancers remains one of the greatest medical challenges of our time. Despite differences in biological mechanisms and sites of onset, these cancers share a common trait: genetic alterations that disrupt cell cycle regulation, leading to an imbalance between proliferation, differentiation, and cell death. The urgency of this challenge, combined with limited treatment options and poor patient prognosis, drives the research of our team. By integrating in vivo models with well-established brain organoid cultures, we accurately replicate both physiological brain development and the pathological mechanisms of tumor formation. Additionally, cutting-edge bioengineering techniques and next-generation organoid models allow us to better mimic patient-specific disease conditions, increasing the precision and clinical relevance of our studies. Our ultimate goal is to uncover the biological mechanisms underlying brain cancers and develop novel therapeutic strategies that improve survival and outcomes for both pediatric and adult patients.

Research directions

  • Modeling Group 4 medulloblastoma and addressing the role of human-specific genes in medulloblastoma pathogenesis

    Medulloblastoma (MB) is the most common pediatric brain cancer and remains a leading cause of morbidity and mortality in children. Traditionally classified into four subtypes (WNT, SHH, Group 3, and Group 4), Group 4 MB is the most prevalent yet the least understood. However, despite its high incidence, Group 4 MB lacks adequate models, limiting our understanding of its biology and potential therapeutic targets. To bridge this gap, we aim to model Group 4 MB pathogenesis in cerebellar organoids by leveraging RNA-seq data from patient samples. Using the Cre-LoxP system and electroporation techniques at defined developmental time points, we will induce the expression of specific oncogenes to replicate disease progression. Additionally, to further elucidate MB pathogenesis, we investigate the role of human-specific genes that are critical for cerebellar development and whose mutations appear to drive MB onset. Understanding these mechanisms could provide valuable insights into novel therapeutic targets for this aggressive pediatric brain tumor.

  • Identification of novel therapies for medulloblastoma and glioblastoma using patient-derived organoids (PDOs)

    Despite the multiple molecular subgroups and subtypes of medulloblastoma (MB), treatment remains largely uniform. Following diagnosis and maximal safe surgical resection, patients undergo a standardized post-operative regimen of radiotherapy and chemotherapy. Similarly, despite the significant inter- and intra-patient heterogeneity of glioblastoma (GB), the standard of care remains maximal safe surgical resection followed by radiotherapy and adjuvant temozolomide. However, in both cases, long-term survival remains a major challenge due to treatment-related toxicities and the risk of secondary neoplasms.

  • This highlights the urgent need for novel therapeutic approaches that enhance survival while minimizing long-term complications. To address this, we employ engineered CAR-T cells targeting novel tumor-specific antigens present a promising immunotherapeutic approach to effectively defeat brain tumors.

  • Bioengineering strategies to enhance brain organoid complexity

    While brain organoids can accurately mimic the structure and function of specific brain regions, they still face limitations, including the absence of key cell types (e.g., blood vessels and immune cells) and the subsequent risk of core necrosis. To address this point, we leverage alginate-based hydrogels in various shapes as a delivery system for diverse cell types, integrating them into both healthy and cancerous brain organoids to enhance their complexity and physiological relevance. Additionally, we aim to develop an innovative biomaterial-based drug delivery system with precise spatial and temporal control, providing new opportunities to identify therapeutic targets for glioblastoma and medulloblastoma.

Group members

  • Luca Tiberi, PI
  • Matteo Gianesello, postdoctoral fellow
  • Valerio Mignucci, postdoctoral fellow
  • Cosimo Sabino, PhD Student
  • Gloria Leva, PhD Student
  • Lucrezia Ciccone, PhD Student
  • Federica Ress, PhD Student
  • Federico Cocchini, pre-doctoral fellow
  • Eleonora Nobilioni, master Student
  • Chiara Bertinat, master Student
  • Ares Palomar, bachelor Student

Grants

  • 2024, EIC-Pathfinder
  • 2023, Fight Kids Cancer
  • 2022, PRIN
  • 2022, Investigator Grant AIRC
  • 2021, EMBO Young Investigator
  • 2019, CARITRO Grant
  • 2018, My First AIRC Grant
  • 2016, Armenise/Harvard Career Development Award

Selected publications

Scientific Articles

Lago C, Federico A, Leva G, Mack NL, Schwalm B, Ballabio C, Gianesello M, Abballe L, Giovannoni I, Reddel S, Rossi S, Leone N, Carai A, Mastronuzzi A, Bisio A, Soldano A, Quintarelli C, Locatelli F, Kool M, Miele E, Tiberi L*. Patient- and xenograft-derived organoids recapitulate pediatric brain tumor features and patient treatments. EMBO Mol Med. 2023 Dec 7. doi: 10.15252/emmm.202318199. * Corresponding author

Lago C, Gianesello M, Santomaso L, Leva G, Ballabio C, Anderle M, Antonica F, Tiberi L*. Medulloblastoma and highgrade glioma organoids for drug screening, lineage tracing, co-culture and in vivo assay. Nature Protocols. 2023 May 29. doi: 10.1038/s41596-023-00839-2. * Corresponding author

Antonica F, Santomaso L, Pernici D, Petrucci L, Aiello G, Cutarelli A, Conti L, Romanel A, Miele E, Tebaldi T, Tiberi L*. A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness. Nature Communications. 2022 Aug 15. doi: 10.1038/s41467-022-32448-0. * Corresponding author

G. Aiello, C. Sabino, D. Pernici, M. Audano, F. Antonica, M. Gianesello, A. Quattrone, N. Mitro, A. Romanel, A. Soldano, L. Tiberi*. Transient rapamycin treatment during developmental stage extends lifespan in Mus musculus and Drosophila melanogaster. EMBO Reports 2022. doi: 10.15252/embr.202255299. * Corresponding author

Antonica F, Aiello G, Soldano A, Abballe L, Miele E and Tiberi L*. (2022) Modeling Brain Tumors: A Perspective Overview of in vivo and Organoid Models. Front. Mol. Neurosci. 15:818696. doi: 10.3389/fnmol.2022.818696. * Corresponding author

Ballabio C, Gianesello M, Lago C, Okonechnikov K, Anderle M, Aiello G, Antonica F, Gianno F, Giangaspero F, Hassan B, Pfister S, Tiberi L*. Notch1 switches progenitor competence in inducing medulloblastoma. Science Advances. 2021 Jun 23. doi: 10.1126/sciadv.abd2781. * Corresponding author

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 Reports. 2019 Dec 17. doi: 10.1016/j.celrep.2019.11.046. *Corresponding author