"The discovery of cancer stem cells has opened up an important new area of research in cancer biology. Support from The Sontag Foundation allows us to enter this field to define the nature of the brain tumor stem cell and the role gene silencing mechanisms play in the ontogeny of medulloblastoma."
- Dr. Laurie Jackson-Grusby
- Assistant Professor of Pathology, Boston Children’s Hospital, Harvard Medical School
About DSA-Funded Research
Methylated Cytosine in DNA is often described as the fifth base in DNA because this small chemical modification functionally alters the genome by shutting down select genes. My work has shown that mutations in the cytosine methyltransferase Dnmt1, which prevent the methylation reaction, exhibit a profound effect of blocking tumor formation in a mouse colon cancer model, cause genome-wide gene de-repression, and cause cell death in a variety of normal mouse cells. In contrast, mouse embryonic stem cells and human colon cancer cell lines can grow indefinitely without the methyltransferase Dnmt1/DNMT1. We hypothesize that the newly identified cancer stem cell component of brain tumors may resolve these seemingly paradoxical effects of loss of Dnmt1/DNMT1. We propose three lines of experiments to 1) test whether medulloblastoma tumor stem cells from Ptch +/-; p53 -/- mice tolerate loss of Dnmt1 while the more differentiated cells in the tumor undergo cell death when Dnmt1 is inactivated, 2) derive embryonic stem cell lines from Ptch +/-; p53 -/- mice to develop an in vitro differentiation assay to discern the requirement for Dnmt1 at the various stages of stem cell and neural progenitor cell differentiation, and 3) test whether loss of Dnmt1 prevents medulloblastomas in Ptch +/-; p53 -/- mice. These multifaceted approaches will examine the notion of a stem cell basis in the formation, and recurrence, of the most common malignant pediatric brain tumor and validate a therapeutic target that regulates gene silencing.
"Laurie is a superb scientist, critical in her thinking and aggressive in her approach to scientific challenges."
Rudolf Jaenisch, M.D.
Whitehead Institute for Biomedical Research
"Laurie is an extremely fast learner, a self starter and grasps the complexities of translational research, both from a technical and commercial perspective?I have seen few young investigators with the drive and 'get it done' attitude that I have observed in Laurie."
Geoffrey Duyk, M.D., Ph.D.