A putative stemness biomarker gene set suggests γ-secretase inhibitor targets self-renewal and pluripotency programs in tumors

B41 Emerging evidence suggests that tumor initiating cell subpopulations bearing characteristics of stem cells may play an important role in drug resistance, tumor recurrence, and metastasis-- major challenges for today9s battle against cancer (1-8). Therefore, it is critical to identify biomarkers for assessing self-renewal and pluripotency programs, or “stemness”activity within tumors. However, it remains a challenge to reliably isolate pure stem cell-like subpopulations of cancer cells based on the activity of stemness using cell surface proteins. We report a novel approach to define a stemness signature by first identifying a set of genes whose expression levels are associated with the changes in self-renewal and pluripotency in both embryonic cells and tumor cell lines. The stemness gene is elevated in genetically manipulated tissue with elevated stem cells numbers. In human cancers, expression of the identified stemness genes is associated with distinct pathological phenotypes and the course of disease progression in breast cancer and chronic myelogenous leukemia. For instance, the expression of stemness genes was significantly anti-correlated with the probability of overall survival and metastasis free survival in retrospective analysis of breast cancer data. This correlation was supported by data from four independent studies. Therefore, our set of stemness genes may not only unveil the feature of stem cells within tumors, but also provide a novel measure of tumor progression and patient prognosis. Finally, we discovered that a γ - Secretase inhibitor (GSI) significantly down-regulated the stemness genes in T-ALL cell lines and in a murine model for breast cancer. These observations are in agreement with recent reports that Notch plays a critical role in regulating the fate of somatic stem cells, including its requirement to maintain the pluripotency and proliferative capacity of stem and progenitor cells at the base of gastrointestinal crypts. Our findings support the idea that GSIs target a sub-population of tumor cells with ectopic stemness activity. These cancer initiating cell sub-populations are thought to evade standard of care treatments with chemotherapy and radiation. Therefore it will be important to determine whether GSIs can provide increased clinical benefit when used in combination with cytotoxic therapies.