Accession Number : AD1017062


Title :   Cell of Origin and Cancer Stem Cell Phenotype in Medulloblastomas


Descriptive Note : Technical Report,01 Jul 2015,30 Jun 2016


Corporate Author : The Jackson Laboratory Bar Harbor United States


Personal Author(s) : Yun,Kyuson


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1017062.pdf


Report Date : 01 Jul 2015


Pagination or Media Count : 12


Abstract : The goal of this project is to test our hypothesis that cells in various stages of maturation in the developing brain produce tumors with distinct biological characteristics when transformed by the same oncogenic event. This hypothesis was based on our observations that certain oncogenes, such as Id2 and constitutively active Notch1 (N1ICD), induced DNA damage and apoptosis when activated in neural stem cells (NSCs) in vivo but had no observable effect when activated in neural progenitor cells (NPCs), immediate progenies of NSCs. These observations indicate that epigenetic changes that occur during NSC-NPC transition somehow block oncogenes from functioning in NPCs. In other words, cellular context in which tumors initiate may have a dominant role over some oncogene function.In addition, we recently reported that cancer stem cells (CSCs)- stem cell like cells in tumors that have stem cell properties and tumor initiating ability- retain epigenetic memories of their cells of origin (Chow et al., 2014). We showed that CSCs derived from NSCs and NPCs depend on different mitogenic and survival pathways, even when they are transformed by the same oncogene in vivo. This finding has multiple implications: one of the most significant being that targeted therapies selected based on bulk tumor cell analysis may be ineffective in eradicating CSCs. We showed in a SHH medulloblastoma model that responsiveness of CSCs to SHH inhibitors therapies varied greatly depending on the cell type in which tumor initiation occurred in vivo. If this novel discovery were generalizable, it would suggest that we will need to analyze CSCs (rare cells in the tumor) and not just the bulk tumor cells (current practice) to identify therapy combinations that will eradicate both CSCs and non-stem (bulk) tumor cells.To directly test whether the cell-of-origin or the activated oncogene itself has more dominant role in determining molecular phenotypes of bulk tumor cells and CSCs, we proposed to gener


Descriptors :   stem cells , brain , brain diseases , therapeutics , cancer research


Distribution Statement : APPROVED FOR PUBLIC RELEASE