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S. John Jacob


Honorary Senior Clinical Research Fellow

  • Consultant Neurologist

John Jacob is a clinican-scientist and a practising clinical neurologist. At different stages of his career he has been funded by personal fellowships or grants from the Wellcome Trust and Medical Research Council. He has also received funding from the Simons Foundation Autism Research Initiative and Cancer Research UK Oxford. Dr Jacob has a background in developmental neurobiology and is interested in how developmental abnormalities give rise to cancer.

Cancer is a collection of many diseases, each with its own unique repertoire of genetic mutations that present many challenges for scientists and clinicians attempting to treat patients. The genetic complexity of cancer means that treatments ultimately need to be tailored to individuals to get the best outcomes. The brain cancer, medulloblastoma (MB) is the commonest malignant brain cancer in children and can also affect adults. In under a decade remarkable progress has been made in distinguishing different types of medulloblastoma, yet the treatment approaches have not changed for many years, and have debilitating side-effects.

A major subtype of medulloblastoma is initiated by activating mutations in the sonic hedgehog (SHH) signalling pathway, which is important for growth, stem cell maintenance, and is implicated in multiple other tumour types. A fundamental limitation is the lack of suitable human cellular SHH-MB models that could be used to test novel drugs. A key missing constituent in existing models is the tumour environment that, in other cancer types, affects tumour growth. Studies in humans show that SHH-MB is genetically heterogeneous, which explains why current therapies have variable outcomes. Therefore, there is an urgent need for new cellular models of SHH medulloblastoma which recapitulate the genetic diversity of the human disease. A major bottleneck in achieving this goal has been the development of robust protocols to generate, in vitro, the tisue of origin of SHH medulloblastoma, the cerebellum. Our collaborators in NDCN and the Sir Willliam Dunn School of Pathology have used advanced stem cell differentiation techniques, to generate cerebellar organoids in vitro from human induced pluripotent stem cells (hiPSC). We have engineered relevant SHH genetic mutations in these organoids using CRISPR and are studying whether SHH-MB can arise de novo in these organoids. With collaborators in the Big Data Institute we will explore, using high throughput single cell sequencing, whether the cerebellar microenvironment affects tumour growth, as in other cancers.