Targeting TGFb Pathway Dependencies in Group 3 Medulloblastoma
Background: Neurons are nerve cells that populate the brain and are responsible for transmitting chemical signals to regulate several human functions. A deadly form of pediatric cancer, known as medulloblastoma, occurs when these neurons start to proliferate uncontrollably. Developing nerve cells, known as neural stem cells, can transform and get ‘stuck’ at a certain stage in brain development. Medulloblastoma is hypothesized to arise from alterations to the DNA template of such neural stem cells, known as mutations. These mutations result in gene expression changes to escalate cellular growth, migration, and invasion. Recent work has identified alterations in the developmental pathway TGFβ, however the functional significance and how it cooperates with other cancer driving events, such as MYC amplification, is currently unclear.
Project Goal: This study aims to mechanistically characterize clinically relevant TGFβ driven genes/pathways in medulloblastoma. I will map the localization of these factors and how they affect gene expression in a panel of tumor cells derived from genetically manipulated neural stem cells driven by MYC alone and/or in combination with TGFβ effectors. I will also investigate how a single cell develops to medulloblastoma and the pathways that mediate this transformation. Finally, I will investigate novel targeted strategies against TGFβ and MYC, some of which are in clinical trials for other cancers. The prognosis for children with this aggressive and treatment resistant medulloblastoma is exceptionally poor. I anticipate that my studies will provide insight on the mechanism(s) of how TGFβ promote tumor progression and new therapies to overcome resistance to improve patient outcomes.
Project Update 2023: Recent work has identified alterations in distinct developmental pathways, MYC and TGFß, in aggressive group 3 medulloblastoma (G3MB). The functional significance of this pathway and how it cooperates with other cancer driving events, such as MYC amplification, is currently unclear. Our studies have focused on using a novel humanized model for MB utilizing induced pluripotent stem cells (iPSC) differentiated to neuroepithelial stem cells (NESC, the presumptive cell of origin for MB. These cells have been genetically engineered to express MYC and/or TGFß pathway effectors identified to be altered in G3MB patients. Excitingly, we discovered that the combination of MYC and TGFß pathway effectors (i) accelerated tumorigenesis and (ii) promoted drug resistance in these cells. By analyzing gene expression and epigenetic profiles from NESCs lines driven by MYC and TGFß pathway effectors, we found a subset of upregulated genes that are targets of the chromatin modifying proteins Polycomb Repressive Complex (PRC). Knockdown of one of these proteins, KDM2B, led to accelerated proliferation and upregulation of MB driver genes. We hypothesize that loss of PRC proteins leads to recruitment of MYC and MYC-cofactors at critical genes/pathways to promote aggressive disease. Using our unique models, we hope to generate critical information on the mechanisms that drive G3MB with important therapeutic relevance.
