Cerebellar Development and Medulloblastoma: New Players and Therapeutic Options

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Background

The cerebellum plays a pivotal role in the coordination of reflex and voluntary movements and in the control of balance and posture, although recent evidence suggests its involvement also in specific cognitive and emotional functions. Cerebellar development begins during early embryonic stages and persists in humans for many months after birth. Its prolonged development into the postnatal period makes the cerebellum susceptible to acquire abnormalities leading to several developmental disorders and cancer. Medulloblastoma (MB), a highly aggressive cerebellar neoplasm, is the most common brain tumor in childhood and a leading cause of pediatric mortality related to the cancer. Despite acceptable survival rates with the current treatment of disease, which includes intensive postoperative radiotherapy and chemotherapy, many survivors undergo devastating long-term side effects, such as secondary malignancies, physical deficits, and severe neuropsychological and neuroendocrine impairments. Thus, new, less toxic and more effective therapeutic options are urgently needed.


MB is a heterogeneous disease, with histopathological and molecular variants with diagnostic relevance. Extensive evidence indicates that MB arises from different cell populations with mutations in developmental pathways required for the physiological maturation of the cerebellar cortex. Dysregulation of cellular processes, such as proliferation, differentiation, migration and survival, in the cells that form the cerebellum can lead to the development of distinct variants of MB. For example, the importance of timing of migration of cerebellar granule cell precursors in the pathogenesis of a molecular subgroup of MB has recently been demonstrated. Therefore, a better understanding of the extracellular cues and intracellular signaling pathways responsible for the physiological development of the cerebellum and, if altered, the initiation and maintenance of MB is critical for the identification of potential drug targets and pharmaceutical agents, which could be proposed as innovative treatment strategies to improve the outcome of patients with MB and the quality of life of survivors. Furthermore, the genetic abnormalities that cause aberrant cerebellar development may be useful for the generation of preclinical MB mouse models which, by mimicking the appearance of the human tumor, allow to test and validate new therapeutic approaches.


This Research Topic aims to explore the molecular biology of MB, focusing on genes, proteins and their regulators within the signaling pathways required for normal cerebellar development and whose alteration may be involved in pathogenesis of MB.
We welcome Original Research, Review, Mini Review and Brief Research Report articles that focus on, but are not limited to:
• latest advances in MB pathophysiology research, including the identification of new molecular targets
• new discovery of signaling pathways or genetic mutations with significant impact on the physiological and pathological development of the cerebellum
• generation of advanced preclinical models for the study of the mechanisms underlying MB formation and growth
• preclinical data, such as in vitro and in vivo tests of good candidates for potential clinical applications in the treatment of MB

Keywords: cerebellar development, medullablastoma

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