Final Report Summary - GLIOMAGENESIS (Molecular and Cellular Mechanisms of Glioma Genesis)
Glioblastoma (GBM) is the most aggressive form of glioma, the most common primary brain cancer in adults. GBM is highly resistant to standard radiotherapy and chemotherapy treatments and thus represents a leading cause of cancer-related death worldwide. Although many genetic alterations have been identified for GBM, its histogenesis is still poorly understood. The relative contribution of each genetic alteration and their downstream effects, as well as the sequence of molecular and cellular events required for tumor formation, are not well known. Dr. Huillard is a junior group leader at the Institut du Cerveau et de la Moelle Epiniere (ICM) in Paris, France. Her group is interested in understanding the cellular and molecular mechanisms that underlie the formation of high-grade gliomas such as GBM. Her previous work has identified the transcriptional regulator Id4 as a factor that inhibits tumor growth and antagonizes the tumorigenic effects of Olig2, a key regulator of GBM development. However, Id4 has also been shown to drive tumorigenesis.
In Aim 1, she proposed to clarify the role of Id4 in gliomagenesis and in adult neural stem cells, the potential cells of origin for GBMs. Her works suggests that Id4 acts as a factor that promotes quiescence of adult neural stem cells and that this function may be conserved in a tumoral setting.
In Aim 2, she proposed to characterize the successive stages leading from the transformation of cells of origin to tumor development, and the individual and combined contributions of defined genetic alterations. Although she initially planned to develop models for high-grade gliomas (such as GBMs), she focused on models of lower grade gliomas (such as oligodendrogliomas), as a result of the strong interactions that she developed with the neuro-oncology group at the institute, led by Pr. Marc Sanson. This collaboration led to the identification of novel mutations in oligodendrogliomas and to the characterization of the function of CIC/Capicua, a gene frequently mutated in these tumors, in oligodendrocyte precursor cells.
In Aim 1, she proposed to clarify the role of Id4 in gliomagenesis and in adult neural stem cells, the potential cells of origin for GBMs. Her works suggests that Id4 acts as a factor that promotes quiescence of adult neural stem cells and that this function may be conserved in a tumoral setting.
In Aim 2, she proposed to characterize the successive stages leading from the transformation of cells of origin to tumor development, and the individual and combined contributions of defined genetic alterations. Although she initially planned to develop models for high-grade gliomas (such as GBMs), she focused on models of lower grade gliomas (such as oligodendrogliomas), as a result of the strong interactions that she developed with the neuro-oncology group at the institute, led by Pr. Marc Sanson. This collaboration led to the identification of novel mutations in oligodendrogliomas and to the characterization of the function of CIC/Capicua, a gene frequently mutated in these tumors, in oligodendrocyte precursor cells.