The effect of growth factor withdrawal on Sox2 expression in SHH medulloblastoma stem cells

Thesis (M.A.)--Boston UniversityMedulloblastomas are the most commonly occurring group of malignant pediatric brain tumors. Over the years, these cerebellar tumors have been histologically and genetically classified to yield a number of distinct subtypes that confer differing disease progression and prognoses. Previous studies on the SHH medulloblastoma mouse model from Jackson-Grusby laboratory have revealed a cancer stem cell origin that may be responsible for the metastatic and more malignant fraction of this subtype. The lab worked with mice harboring mutations in tumor suppressor genes Ptch1 and p53. A novel discovery from this background was that mouse cerebellum deficient in p53 and heterozygous for the SHH pathway inhibitor gene Ptch1 developed an aberrant stem cell population predisposed to malignant progression through Ptch1 loss-of- heterozygosity (LOH). To study this tumor initiating population of stem cells, the lab has constructed a Ptch1 heterozygous, p53 deficient mouse model which reliably provided mice with aberrant cerebellar stem cells (pre-LOH) and cancer stem cells (post-LOH). Sox2, a neural stem cell marker and transcription factor for stem cell maintenance, has been indicated as a prospective marker to isolate these different Ptch1;p53 stem cells. To characterize the marker’s ability to detect the stemness of the differing SHH medulloblastoma stem cells, previous studies in the lab measured Sox2 antibody levels by inducing differentiation through growth factor withdrawal. The finding was that Sox2 levels were maintained in the cancer stem cell population, indicating a resistance to differentiation, while Sox2 levels dropped in the aberrant stem cell population, indicating the ability to differentiate. [TRUNCATED