Our Science – Hou Website

Steven X. Hou, Ph.D.

Mouse Cancer Genetics Program Head, Stem Cell Regulation and Animal Aging Section Senior Investigator Building 560, Room 12-70 NCI-Frederick Frederick, MD 21702-1201 Phone:   301-846-1589 Fax:   301-846-6145 E-Mail:   shou@mail.ncifcrf.gov

Biography

Dr. Steven Hou received his Ph.D. from the University of Chicago in 1994 and completed postdoctoral training with Dr. Norbert Perrimon at Harvard Medical School in 1997. He became a Tenure-track Investigator at NCI-Frederick in September 1997 and received tenure as a Senior Investigator in May 2006.

Research

Molecular Genetic Study of Stem Cell and Cancer Stem Cell Regulation in Drosophila and Mice

Tissues and organs are generated and maintained by stem cells. Similarly, tumors may originate from a few transformed cells with stem-cell characteristics, called cancer stem cells. Stem cells have immense potential for therapeutic use in regenerative medicine and as targets for anticancer therapies. To make use of this potential, we must first understand the molecular parameters that define a stem cell and the mechanisms that regulate stem-cell behavior.

My group is engaged in the molecular genetic study of stem cell and cancer stem cell regulation in Drosophila and mice. The powerful genetic manipulations available in Drosophila will enable us to dissect the basic biological processes of stem cell regulation. Extending the findings from the fly to the mouse is intended to help enable us to develop better models for human diseases.

Our current projects have evolved from our earlier studies of the JAK/STAT signal transduction pathway in Drosophila. As a postdoc, I identified mutations in the Drosophila stat gene and developed a fly model to study the JAK/STAT signal transduction pathway (Hou et al., Cell, 1996). After I moved to NCI, my group identified a receptor for the JAK/STAT signal transduction pathway (Chen et al., Genes Dev., 2002) and found that the JAK/STAT pathway and Cyclin D/Cdk4 cooperatively regulate tumor development in fly blood and eye (Chen et al., Dev. Cell, 2003). Over the course of our studies, we accumulated a number of reagents for studying JAK/STAT signaling in Drosophila. Using these tools, we demonstrated that a RapGEF/Rap signaling regulates stem cell anchoring to the niche through interactions with the JAK/STAT signal transduction pathway (Wang et al., Dev. Cell, 2006). We also identified adult kidney multipotent renal and nephric stem cells (RNSCs) in Drosophila Malpighian tubules (MTs) and demonstrated that an autocrine JAK/STAT signal regulates the kidney stem cell self-renewal (Singh et al., Cell Stem Cell, 2007).

We performed a genetic screen for mutations in the MTs and have so far identified mutations in 20 genes that affect the RNSC fates. Mutations in 12 of them caused RNSC overproliferation without differentiation, and resulted in the formation of migratory cancer stem cells. We obtained the opposite phenotype as well in mutations of other 8 genes, which caused the early differentiation of RNSCs.

Our first project is to investigate how the two groups of genes regulate the adult kidney stem cell fates in the Drosophila model system. Our second project is to extend our findings from the Drosophila MTs to the mouse kidney. We have obtained or are in the process of generating a conditional knockout mouse for the mouse homologues of the fly genes that regulate RNSC fates. We will study these genes’ function in mouse kidney stem cells and cancer stem cells. We are also developing a mosaic expression and analysis with double markers (MEADM) technique for lineage tracing and to study the corresponding mouse homologues of the fly kidney stem cell genes in mouse kidney stem cell regulation. We have also identified the mouse RapGEF2 as the homologue of the fly RapGEF and generated RapGEF2 conditional knockout mice. The RapGEF2-deficient mice have vascular and specific stem cell defects. Our third project is to study RapGEf2’s functions in angiogenesis and tumor formation using the RapGEF2-deficient mice.


In summary, we have already laid the groundwork for both fly and mouse projects, and expect to reap the results in the next few years. Using this cross-species approach we expect both to obtain an enhanced understanding of stem-cell regulation and to identify new targets for the treatment of human diseases.

This page was last updated on 6/11/2008.