Department of Medicine
Division of Genetics
New Research Building, Room 458E
77 Avenue Louis Pasteur
Boston, MA 02115
The broad interest of Li laboratory is stem cells and cancer. In particular, we are interested in elucidating how cells of origin contribute to the cancer phenotype, as well as how cancer stem cells (CSCs, also known as tumor-initiating cells, or tumor-propagating cells) evolve from normal target cells of cancer, and how they 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 approaches to treat and/or to prevent cancer. Current projects include:
Cells of origin in breast cancer: We are using several complementary approaches in genetically modified mice, including Cre-lox genetic marking and in vivo cell fate mapping, as well as cell sorting coupled with fat pad transplantation, to study how cells of origin contribute to the heterogeneity of breast cancer. By applying lineage-tracing approaches, we follow progression of normal cells (i.e., cells of origin) to premalignant cells, and eventually to cancer cells. By flow cytometry and genomic approaches, we aim to identify and to validate key mutations and deregulated pathways at different stages of cancer progression, leading to the formation of CSCs, in animal models.
ERG and ETV1 in stem cells and cancer: ERG and ETV1 are ETS family transcription factors playing central roles in both normal development (e.g., ERG in hematopoietic stem cells) and disease, particularly in prostate cancer. They are overexpressed in >50% of human prostate cancer cases due to TMPRSS2-ETS gene fusions. We are using knockin mouse models to study roles of ERG and ETV1 in prostate tumorigenesis and to identify their cooperating oncogenic pathways. We are also using conditional approaches to study the role of Erg in normal and malignant stem cells in mice.
Developmental stage-specific programs in leukemogenesis: Down syndrome acute megakaryoblastic leukemia (DS-AMKL) is a unique pediatric leukemia characterized by fetal cell origin, trisomy 21, and GATA1 mutations. We defined a developmental stage-specific program that explains the strict restriction of DS-AMKL to children. This includes overactive IGF/IGF1R signaling and overexpression of a microRNA gene on human chromosome 21, miR-125b-2. Currently, we are investigating whether fetal and adult stages of hematopoiesis have different dependencies on IGF/IGF1R signaling and whether such difference is utilized by certain hematopoietic cells to drive their leukemic transformation. We also study the role of miR-125b-2 in leukemogenesis.
Transcription network in epithelial cells: We are developing a new project to explore the transcription network in epithelial cells and to understand how perturbation of the network contributes to cancer. We are using 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.
Klusmann JH, Godinho FJ, Heitmann K, Maroz A, Koch ML, Reinhardt D, Orkin SH, Li Z. Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes Dev.
Klusmann J-H*, Li Z*, Böhmer K, Maroz A, Koch ML, Emmrich S, Godhinho FJ, Orkin SH, Reinhardt D. miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia. Genes Dev. 2010;24(5):478-90. (*co-first author)
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. (*co-first author)
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.
For a complete listing of publications click here.
Last Update: 8/16/2012