We have developed several novel approaches for analysis of massively parallel gene expression datasets. First, StepMiner, a tool that identifies 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 differentiation, 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), first, 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 fifth 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 specific 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.

Public Health Relevance

Identification 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, identification 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 identification 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 findings will be relevant to the mission of the NIH because it has a direct impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
5K99CA151673-02
Application #
8294521
Study Section
Subcommittee G - Education (NCI)
Program Officer
Schmidt, Michael K
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$152,135
Indirect Cost
$11,269
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Pan, Ying; Volkmer, Jens-Peter; Mach, Kathleen E et al. (2014) Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci Transl Med 6:260ra148
Voskoboynik, Ayelet; Newman, Aaron M; Corey, Daniel M et al. (2013) Identification of a colonial chordate histocompatibility gene. Science 341:384-7
Wu, Bo; Sahoo, Debashis; Brooks, James D (2013) Comprehensive gene expression changes associated with mouse postnatal kidney development. J Urol 189:2385-90
Volkmer, Jens-Peter; Sahoo, Debashis; Chin, Robert K et al. (2012) Three differentiation states risk-stratify bladder cancer into distinct subtypes. Proc Natl Acad Sci U S A 109:2078-83
Willingham, Stephen B; Volkmer, Jens-Peter; Gentles, Andrew J et al. (2012) The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 109:6662-7
Dalerba, Piero; Kalisky, Tomer; Sahoo, Debashis et al. (2011) Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 29:1120-7