The current focus of our lab research is cancer stem cells (CSCs), rare stem-like cells in the tumors responsible for maintaining tumor homeostasis, driving tumor progression, and mediating tumor recurrence and metastasis. The laboratory has the following interconnected research projects.

1. Identification and characterization of prostate cancer stem/progenitor cells  Using a combination of cell surface marker (CD44, CD133, integrin a2b1, ABCG2, etc) staining and other techniques (e.g., side population or SP analysis; label-retaining cell or LRC identification), we have established a model of hierarchical organization of tumor cells in PCa xenografts (Cancer Res., 65, 6207-6219, 2005; Oncogene 25, 1696-1708, 2006; Mol. Carcinogenesis, 46, 1-14, 2007; Cancer Res. 67, 6796-6805, 2007; Cancer Res. 68, 1820-1825). We are currently testing the validity of this model in patient prostate tumors. Eventually we wish to obtain the unique gene expression profiles of prostate tumor-initiating cells.

2. Mechanisms of CSC self-renewal  Our studies indicate that NanogP8, a Nanog homolog derived from retrotransposition and specifically expressed in cancer cells, plays an essential role in regulating CSC self-renewal.

3. Mechanisms of cancer stem/progenitor cell division  Emerging data suggest that undifferentiated CSCs preferentially undergo asymmetric cell division whereas differentiated tumor progenitor cells undergo exclusively symmetric cell division.

4. miRNA regulation of prostate CSCs and tumor development  miRNAs play a critical role in regulating normal stem cell pluripotency, proliferation, and differentiation. Our studies indicate that miRNAs are also intimately involved in regulating prostate cancer stem/progenitor cell properties as well as prostate tumor development.

5. Involvement of CSCs in metastasis   It is becoming increasingly clear that the rare tumor cells endowed with the ability to disseminate and metastasize into distant organs may actually be CSCs. We are using several prostate cancer xenograft models as well as primary tumor-derived cells to test this possibility. Our accumulated data suggest that in fact, metastatic CSCs might represent a subset of CSCs (i.e., metastatic cancer cells are more rare than CSCs) and that tumor cells implanted orthotopically express a unique ‘metastatic gene signature’ that allows manifestation of the metastatic potential.

6. CSC resistance to therapeutics  Conventional wisdom is that cancer cell resistance to therapeutics is acquired through genetic alterations such as gene amplifications, deletions, and/or mutations. We are testing the hypothesis that drug resistance is caused, at least in part, through a selection and subsequent expansion of the pre-existing stem-like tumor cells.

7. Normal human prostate (NHP) stem/progenitor cells and their involvement in tumorigenesis  Several NHP stem/progenitor cell populations have been reported. Our lab has been studying their immunophenotypic, developmental, proliferative, and senescence properties hoping to obtain novel insights on their involvement in tumor development.

Our ultimate goal is to uncover the unique properties of CSCs and then design specific therapeutic strategies to eradicate tumors.