Altering master genetic regulators SNF5/INI1 and LIN28A to model and treat atypical teratoid/rhabdoid tumors
Pediatric atypical teratoid/rhaboid tumors (ATRT) are among the most deadly malignant pediatric brain cancers. The hallmark of these cancers is mutation or deletion of the SNF5/INI1 gene, which can turn on or off many other genes. We have recently identified the stem cell factor LIN28A, also a regulator of many other genes, as being highly expressed in ATRT. This proposal will investigate the role of master control genes LIN28A and SNF5/INI1 in the development of ATRT. To do this, we will overexpress LIN28A and disrupt expression of SNF5/INI1 in normal human stem cells derived from the cerebral cortex and cerebellum. Because key genetic alterations found in pediatric ATRT will be used, and our unique culture system contains the stem cell types from which pediatric ATRT are thought to arise, we can create accurate models for these tumors. We will test the tumor forming capabilities of our model in cell culture and by injecting the cells into the brains of mice. To prove the importance of master gene regulators, we will also use short-hairpin RNA to disrupt expression of LIN28A in ATRT cell lines, which express high levels of LIN28A, to see if we can block growth and tumor formation. Our proposal will allow for rapid progress to be made in treating patients with ATRT, because a better understanding of how ATRT arises will allow us to devise improved therapies. Proving that LIN28A is essential for ATRT will allow researchers to focus on this gene as an "Achilles' heel" for ATRT.