Medulloblastoma and Cerebellar Developmental Disorders
Using stem cell lines to gain insight into overproliferation leading to brain tumors and malformations
Kathleen J. Millen, PhD, studies the genetic basis of early brain development, particularly in the cerebellum, which is important to motor control, attention, language and emotion. The Millen lab is the first lab in the world to focus on human cerebellar development.
During development, genes control tissue development, and when processes go awry, neurodevelopmental disorders result. One such disorder is medulloblastoma (MB), which is a cell overproliferation that causes cancer. MB comprises a group of malignant cerebellar embryonal neoplasms and represents 15-20% of pediatric brain tumors. MB occurs most commonly in children between 3 and 8 years but can occur in children or adults at any age.
Millen and team were the first to identify the human stem cells that lead to the most common form of MB, which are called rhombic lip cells. The rhombic lip gives rise to most of the neurons in the brain, which explains why MB is the most common malignant pediatric brain tumor. This important step in identifying the stem cells involved is a leap forward in the quest for earlier detection, more effective treatments and more cell-specific targeted treatment approaches.
Knowing the cells of origin for MB and their gene expression profiles, Millen and team are researching how to drive induced pluripotent stem cells (iPSCs) to specific cell fates as a way to identify cancer drug targets.
Together with Dr. Kimberly Aldinger, the Millen lab developed the Developmental Cell Atlas of the Human Cerebellum, with -omics and imaging data on human cerebellar development. Studies show striking differences between mouse and human cerebellar development, highlighting the importance of knowledge, expertise, and resources such as the atlas for understanding and treating human brain diseases, including MB.
Millen is interested in industry partnerships to collaborate on animal models and mapping cell fates involved in MB and other pediatric brain cancers as well as neurodevelopmental disorders to develop more successful and targeted therapies.
Stage of Development
- Pre-clinical in vitro or in vivo
- Collaborative research and development
- Consultation agreement
- Sponsored research agreement
- Animal models
- Data access
- Hendrikse LD, Haldipur P, Saulnier O, ... Millen KJ, Taylor, MD. Failure of human rhombic lip differentiation underlies medulloblastoma formation [published correction appears in Nature. 2022 Dec;612(7940):E12]. Nature. 2022;609(7929):1021-1028.
- Smith KS, Bihannic L, Gudenas BL, ... Millen KJ, Northcott, PA. Unified rhombic lip origins of group 3 and group 4 medulloblastoma. Nature. 2022;609(7929):1012-1020.
- Haldipur P, Millen KJ, Aldinger KA. Human cerebellar development and transcriptomics: implications for neurodevelopmental disorders. Annu Rev Neurosci. 2022;45:515-531.
- Aldinger KA, Thomson Z, Phelps IG, ... Millen KJ. Spatial and cell type transcriptional landscape of human cerebellar development. Nat Neurosci. 2021;24(8):1163-1175.
- Aldinger KA, Timms AE, Thomson Z, … Millen KJ, et al. Redefining the etiologic landscape of cerebellar malformations. Am J Hum Genet. 2019;105(3):606-615.
- Haldipur P, Millen KJ. What cerebellar malformations tell us about cerebellar development. Neurosci Lett. 2019;688:14-25.
- Haldipur P, Aldinger KA, Bernardo S, ... Millen KJ. Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum. Science. 2019;366(6464)454-460.