? DESCRIPTION (provided by applicant): The association of ionizing radiation (IR) exposure with increased cancer incidence has been recognized for over 100 years, although the mechanism remains poorly understood. IR-induced cancers are conventionally attributed to the direct generation of cancer-causing mutations resulting from IR-mediated DNA damage. Our lab has developed an evolutionary based model for carcinogenesis, which instead highlights a role for cellular fitness as a major force in tumor suppression. Basically, we propose that healthy cells in a healthy tissue are very good at maintaining the status quo, as these highly fit cells effectively compete against mutant cells, rendering most potentially oncogenic mutations disadvantageous in terms of clonal selection. From an evolutionary standpoint, this alternative Adaptive Oncogenesis model predicts that investment in tissue fitness maintenance should be a major tumor suppressive strategy that ensures rare cancer incidence in the young, thus increasing organismal population success. We propose that besides direct generation of DNA damage, IR exposure or other insults, by decreasing cell fitness, create room for improvement, and thus promote the expansion of cells with oncogenic mutations that become adaptive in this altered context. Using mouse models, we will test the hypothesis that IR exposure leads to sustained Nrf2 activation in hematopoietic stem cells (HSC), and that while Nrf2 protects cells from excessive damage by activating anti-oxidant players, it also activates pro-differentiation players, thus leading to loss of stemness. We will also explore the mechanism underlying sustained Nrf2 activation in previously irradiated HSC, as well as how the activation of pathways such as Notch can reverse Nrf2 activation and restore self-renewal. We propose that this Nrf2-mediated programmed mediocrity, at least in the more natural context of damage to the occasional cell, facilitates the elimination of the damaged cell from the stem cell pool. Maintaining stem cell pool fitness should be tumor suppressive by limiting selection for adaptive oncogenic mutations. On the other hand, under the more modern context of total body or whole tissue radiation exposure, virtually all surviving stem cells may have experienced genotoxic stress, and thus the Nrf2-dependent programmed mediocrity will reduce the fitness of the entire stem cell pool (more fit competition will be lacking), which can promote selection for adaptive oncogenic mutations.

R21CA179501

2014-12-18

2016-11-30