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.

Agency
National Institute of Health (NIH)
Type
Research Transition Award (R00)
Project #
4R00CA151673-03
Application #
8901596
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Li, Jerry
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Chen, James Y; Miyanishi, Masanori; Wang, Sean K et al. (2016) Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530:223-7
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; 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
Dalerba, Piero; Sahoo, Debashis; Clarke, Michael F (2016) CDX2 as a Prognostic Biomarker in Colon Cancer. N Engl J Med 374:2184
Chan, Charles K F; Seo, Eun Young; Chen, James Y et al. (2015) Identification and specification of the mouse skeletal stem cell. Cell 160:285-98
Cheah, Ming T; Chen, James Y; Sahoo, Debashis et al. (2015) CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. Proc Natl Acad Sci U S A 112:4725-30
Shin, Kunyoo; Lim, Agnes; Zhao, Chen et al. (2014) Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26:521-33
Dimov, Ivan K; Lu, Rong; Lee, Eric P et al. (2014) Discriminating cellular heterogeneity using microwell-based RNA cytometry. Nat Commun 5:3451