We have developed several novel approaches for analysis of massively parallel gene expression datasets. First, StepMiner, a tool that identi?es step-wise transitions in the time course microarray datasets. Second, BooleanNet, a method of discovering Boolean implications between genes using these large numbers of gene expression datasets. Recently, we published a new method called MiDReG (Mining Developmentally Regulated Genes) that uses Boolean implications to successfully predict genes in developmental pathways. By initially applying this approach to lymphocyte differentitaion, we discovered previously unrecognized markers for B cell differentiation, as well as a novel branchpoint of B cell and T cell development. The proposed project will build on our successful prediction of human B cell developmental genes using MiDReG to develop a general method for discovering cancer stem and progenitor cells. I am planning to validate this approach in human bladder cancer (Transitional Cell Carcinoma), ?rst, because it is a simple model cancer to test, and, second, because our laboratory has the expertise to isolate and test cell populations for tumor-initiating potential. This method will be optimized for the discovery of stem and progenitor cells in bladder cancer and hopefully it will serve as a starting point for similar studies in other types of cancers. More than 90% of human bladder cancers arise from a simple epithelial tissue called urothelium, and are commonly called transitional cell carcinomas (TCC). Furthermore, human bladder cancer is ?fth most common cancer in the United States. Our laboratory has established a working model for the xenotransplantation of human bladder cancer in mice and has recently discovered a tumor-initiating population in bladder cancer. Recent studies show that cancer is heterogeneous and forms a hierarchy of original tumor cell populations. However, a detailed bladder cancer developmental hierarchy remains unknown. My primary near-term goal in this proposal is to understand this hierarchy of bladder cancer cells using a systems biology approach to predict (diagnostic/prognostic) genes that mark speci?c populations. I will validate this approach using human cancer tissue microarrays in collaboration with Dr. Matt van de Rijn ,and using xenotransplantation in collaboration with Drs. Robert Chin and Jens-Peter Volkmer. In the longer term, I will extend the method to identify stem and progenitor cells in other types of cancers during my independent investigator phase.
Identi?cation of cancer stem and progenitor cells contributes strongly to the understanding of development and differentiation of cancer. Cancer stem cells may be at the core of the resistance of cancers to conventional therapies, and are thus likely the target of future cancer treatments. Also, identi?cation of cancer stem cells may aid in understanding the normal developmental process. Tissue stem cells have long term regenerative potential that may be used to regenerate injured or diseased organs. The identi?cation of hematopoietic stem cells, for example, has substantially changed both how we understand the normal developmental process and how we approach treatment of hematological disease. Knowledge about these cells will play a pivotal role in developing better ways to combat human diseases. Our ?ndings will be relevant to the mission of the NIH because it has a direct impact on human health.
| Sereti, Konstantina-Ioanna; Nguyen, Ngoc B; Kamran, Paniz et al. (2018) Analysis of cardiomyocyte clonal expansion during mouse heart development and injury. Nat Commun 9:754 |
| Sahoo, Debashis; Wei, Wei; Auman, Heidi et al. (2018) Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer. Oncotarget 9:6550-6561 |
| Kahn, Suzana A; Wang, Xin; Nitta, Ryan T et al. (2018) Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma. Nat Commun 9:4121 |
| Cai, Shang; Kalisky, Tomer; Sahoo, Debashis et al. (2017) A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. Cell Stem Cell 20:247-260.e5 |
| Sin, Mandy L Y; Mach, Kathleen E; Sinha, Rahul et al. (2017) Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics. Clin Cancer Res 23:3700-3710 |
| Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi et al. (2017) The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity. Am J Physiol Lung Cell Mol Physiol 312:L861-L872 |
| Dalerba, Piero; Sahoo, Debashis; Paik, Soonmyung et al. (2016) CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med 374:211-22 |
| Skelton, Rhys J P; Brady, Bevin; Khoja, Suhail et al. (2016) CD13 and ROR2 Permit Isolation of Highly Enriched Cardiac Mesoderm from Differentiating Human Embryonic Stem Cells. Stem Cell Reports 6:95-108 |
| Krampitz, Geoffrey Wayne; George, Benson M; Willingham, Stephen B et al. (2016) Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors. Proc Natl Acad Sci U S A 113:4464-9 |
| Dalerba, Piero; Sahoo, Debashis; Clarke, Michael F (2016) CDX2 as a Prognostic Biomarker in Colon Cancer. N Engl J Med 374:2184 |
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