Mechanisms Underlying the Responses of Normal and Cancer Stem Cells to Environmental and Therapeutic Insults
New Faculty II
$2 274 368
Statement of Benefit to California:
This proposal is focused on mechanisms by which stem cells respond to DNA damage. Such damage can impact stem cell function and lead to organ failure or cancer development. The applicant proposes to use hematopoietic stem cells (HSC) as a tractable model system to examine repair or apoptotic responses resulting from DNA damage. The applicant has developed a mouse model of human leukemia in which the cancer stem cell (CSC) population arising from the HSC compartment can be identified and tracked. This model will be used to understand how deregulation in apoptosis and DNA repair contribute to cancer development. These studies may provide insight into fundamental mechanisms that regulate development of normal HSC’s and CSCs and could facilitate identification of possible therapeutic targets for the treatment of cancer. In specific Aim 1 the applicant proposes to determine the role of apoptosis in maintaining normal numbers of stem and progenitor cells during hematopoiesis. In the preliminary studies the applicant demonstrated a differential effect of radiation on the induction of apoptosis in stem cells as compared with progenitor cells. The applicant proposes to expand these observations to in vitro experiments in which pro-survival factors will be eliminated from the culture media. In specific Aim 2, the ability of stem cells and progenitor to repair their DNA in response to injury will be determined. In Aim 3, the applicant will use in vitro methods to identify mediators of apoptosis and DNA repair which are deregulated in cancer cells. Reviewers judged this proposal to be novel and well written. It encompasses state-of-the-art technology and methodology. All of the technical aspects associated with the experiments are already established in the applicant’s lab. The use of highly enriched, defined cell populations was considered a promising approach that will greatly facilitate the interpretation of results. The proposal contains thorough descriptions of potential pitfalls and alternative approaches to follow if problems arise. The mouse model was considered particularly appropriate, since it readily correlates with human disease in the setting of myeloproliferative disorder. Reviewer’s had concerns that it may be difficult to obtain sufficient numbers of rare cell subtypes needed for some of the experiments and whether “single exposure” experiments will accurately reproduce cancer characteristics typically associated with a “multi-hit” phenomenon. Additionally, there was some concern that in vitro responses to DNA damage might not reflect activity or apoptotic responses in vivo. The applicant has had excellent postdoctoral training in two well established labs. He/she has an outstanding publication record in high impact journals. The applicant’s current focus is on cancer stem cells and hematopoietic stem cells. Strong career development and mentorship plans were proposed. The environment and institutional support for the proposed studies are excellent.