Biological and Biomedical Science
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Zhe Li

Department of Medicine

Division of Genetics
Brigham and Women's Hospital
New Research Building, Room 466B
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4740
Fax: (617) 525-4705
Email: zli4@rics.bwh.harvard.edu

The broad interest of Li laboratory is stem cells and cancer. We are particularly interested in understanding how cancer stem cells (CSCs, also known as tumor-initiating cells, or tumor-propagating cells) evolve from normal target cells of cancer through accumulation of mutations and through interaction with microenvironments, as avenues for identifying pathways unique to them. We are also interested in exploring how CSCs can be instructed to differentiate. We study these by applying concepts and tools from stem cell biology and developmental biology, and by using a combination of mouse genetics, biochemistry, and genomic approaches. The long-term goal is to develop novel therapeutic approaches targeting CSCs. Current projects in our laboratory include:

Breast cancer stem cells and their cellular origins:
We recently generated a novel mouse model of human breast cancer initiated by the t(12;15) ETV6-NTRK3 chromosomal translocation. It provides a unique opportunity to identify the affected population of cells early in the evolution of cancer. Currently, we are using this model to identify and characterize genetically marked target cells of cancer, premalignant cells, and CSCs. By flow cytometry and genomic approaches, we will identify additional mutations and deregulated pathways leading to the formation of CSCs, and validate them in mouse models.

Mouse models of prostate cancer with TMPRSS2-ERG gene fusions:
TMPRSS2-ERG gene fusions are frequently identified in human prostate cancer. Many of these fusions are generated through an interstitial deletion between TMPRSS2 and ERG, which are only ~3Mb apart on human chromosome 21. We are using knockin mouse models to understand contributions of ERG as well as deletion of genes between Tmprss2 and Erg to prostate tumorigenesis. Future studies will also include characterizing the relation between Tmprss2-Erg fusion and prostate stem/progenitor cells in driving prostate cancer development.

The role of Erg in normal and malignant stem cells:
Erg is an ETS family transcription factor playing critical roles in both normal development and disease, especially in prostate cancer. In this study, we are using a conditionally rescuable Erg knockdown mouse model to study its role in normal and malignant stem cells in adults.

Transcription network in epithelial cells:
We are developing a new project to explore the transcription network in epithelial cells and understand how perturbation of the network contributes to cancer. We will use a metabolic biotin tagging system, coupled with mass spectrometry and ChIP analysis, to study this. Currently, we are establishing a GATA3-centered transcription network in breast cancer cells.

 

 

References:

  • Li Z, Tognon CE, Godinho FJ, Yasaitis L, Hock H, Herschkowitz JI, Lannon CL, Cho E, Kim S-J, Bronson RT, Perou CM, Sorensen PH, Orkin SH. ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex. Cancer Cell. 2007;12(6):542-58.

  • Li Z, Chen MJ, Stacy T, Speck NA. Runx1 function in hematopoiesis is required in cells that express Tek. Blood. 2006;107(1):106-10.

  • Li Z, Lukasik SM, Liu Y, Grembacka J, Bielnicka I, Bushweller JH, Speck NA. A mutation in the S-switch region of the Runt domain alters the dynamics of an allosteric network responsible for CBFβ regulation. J Mol Biol. 2006;364(5):1073-83.

  • Li Z, Godinho FJ, Klusmann J-H, Garriga-Canut M, Yu C, Orkin SH. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor – GATA1. Nat Genet. 2005;37(6):613-9.