The current focus of our lab research is cancer stem cells (CSCs), stem-like cancer cells in the tumor thought to be the cells that maintain tumor homeostasis, drive tumor progression, and mediate drug resistance, 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 α2β1, ABCG2, etc) staining and other techniques (e.g., side population or SP analysis; label-retaining cell or LRC; Aldefluor assays; cell size selections), 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, 2008; Stem Cells 27: 993-1005, 2009). 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 and PCa development (Stem Cells 27: 993-1005, 2009).

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 (see Li et al. for a recent review).

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 (see Honorio et al, 2009). Our lab has been studying their immunophenotypic, developmental, proliferative, and senescence properties (Bhatia et al., 2005; Bhatia et al., 2008) 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.