Determining the functional role of Sept9 phosphorylated isoforms in Sonic Hedgehog Medulloblastoma

Proteins are the molecular machines of our cells. They can be controlled by adding tag groups called phosphates. In healthy cells, this phosphorylating system keeps cellular processes running smoothly. In cancer, however, this system is broken, where proteins are mistagged, leading to cancer cells growing uncontrollably. Previous our lab found that in medulloblastoma, the most common malignant pediatric brain cancer, there were more harmful phosphorylated versions of some proteins compared to normal precursor cells. One of these proteins was Septin-9 (SEPT9). The role SEPT9 plays in the cancer cells remains unclear. To address this, we are assessing the role that the phosphorylated SEPT9 plays in Sonic Hedgehog medulloblastoma (SHH MB). To investigate the difference of harmful phosphorylated protein versions in medulloblastoma (MB) cells compared to normal granule neuron precursors (GNP), we used a mouse model of medulloblastoma. MB cells which either lack harmful versions of these proteins or overexpress them are being developed. We have shown that there are greater amounts of harmful versions of Sept9 in SHH MB cells compared to GNPs. To assess the role of these harmful versions, we are creating cell models that either reduce the amount of mistagged proteins or have increased amounts. These models are called knockdown (KD) and overexpression (OE) models respectively and will be used to determine the functional role that Sept9 phosphorylated isoforms play in SHH MB. This work may unveil a way cancer cells grow by altering which versions of proteins are present. Ongoing work will help us understand exactly how these proteins support cancer cells and may point towards new therapies targeting rogue versions of proteins in cancers.