(1) The Wnt and BMP signaling pathways in stem cell proliferation and differentiation. It has been well established that both Wnt and BMP signaling pathways play an important role in development, as well as in embryonic and adult stem cell differentiation. However, the precise mechanisms through which these signals exert their biological functions remain to be fully elucidated. Using the pluripotent mesenchymal stem cells (MSCs) as a model system, we have demonstrated that the 14 types of BMPs exhibit distinct roles in regulating linage commitments of MSCs. We have also illustrated the distinct functions of the 19 Wnt factors in regulating lineage-specific differentiation of MSCs. Furthermore, there is a cross-talk between Wnt and BMP signaling pathways. We are interested in identifying the key signaling mediators that regulate stem cell proliferation and differentiation and that control the divergences of different lineages.

(2) Defects in stem cell differentiation and tumorigenesis. As our knowledge about stem cells and cancer stem cells expands, it has become increasingly evident that cancer is not just a genetic disease but also a differentiation disease. The essence of genetic and epigenetic changes in cancer cells is intended to disrupt the differentiation pathways in the affected cells. Using primary bone tumor (aka, osteosarcoma, a type of malignant pediatric tumors occurring at the growth plates of adolescent long bones) as a model system, we have found that bone tumor cells fail to undergo terminal differentiation, when compared with the normal preosteoblast progenitors. In fact, the bone tumor cells are refractory to differentiation signals, and even convert differentiation cues into proliferation signals. We are interested in identifying the critical differentiation defects that may hold the keys to unlock the pathogenesis of human tumors.

(3) Interactions between tumors and stromal cells in the development of bone metastasis. Tumor microenvironment and cancer metastasis are two important but often overlooked areas in cancer research. Metastatic cells are a subset of primary tumor cells that have acquired the ability to complete a multi-step metastatic cascade, including migration, dissemination, extravasation, and eventual proliferation at a discontinuous secondary site. Increasing evidence suggests that the interactions between disseminated cancer cells and bone marrow stromal cells (also referred to as bone marrow mesenchymal stem cells, bMSCs) may play an important role in controlling the survival and colonization of bone metastasis. Using our unique bone metastasis animal models, we are interested in identifying and elucidating the roles of bMSC-derived factors in the development of bone metastasis (from breast cancer, prostate cancer, etc).

(4) Targeted therapies and regenerative medicine. The ultimate goal of biomedical research is to translate basic findings from bench to bedside. Identification of differentiation defects in tumors would allow us to develop novel differentiation therapies that circumvent the defective stages. Accordingly, the bMSC-derived factors may serve as cancer drug targets. The critical regulators of stem cell proliferation and differentiation may be used as therapeutic genes for stem cell-based and/or gene therapies for tissue regeneration (such as bone and cartilage regeneration and tendon injury repair) and for the treatment of other bone and musculoskeletal disorders.

Selected Papers

He BC, Gao JL, Zhang BQ, Luo Q, Shi Q, Kim SH, Huang E, Gao Y, Yang K, Wagner ER, Wang L, Tang N, Luo J, Liu X, Li M, Bi Y, Shen J, Luther G, Hu N, Zhou Q, Luu HH, Haydon RC, Zhao Y, He TC (2011) Tetrandrine Inhibits Wnt/b-Catenin Signaling and Suppresses Tumor Growth of Human Colorectal Cancer. Molecular Pharmacology published ahead of print October 26, 2010, doi:10.1124/mol.110.068668 PMID: 20978119

Rastegar F, Gao JL, Shenaq D, Luo Q, Shi Q, Kim SH, Jiang W, Wagner ER, Huang E, Gao Y, Shen J, Yang K, He BC, Chen L, Zuo GW, Luo J, Luo X, Bi Y, Liu X, Li M, Hu N, Wang L, Luther G, Luu HH, Haydon RC, He TC (2010) Lysophosphatidic acid acyltransferase b (LPAATb) promotes tumor growth of human osteosarcoma. PLoS ONE 5(12): e14182. doi:10.1371/journal.pone.0014182, PMID: 21152068

Luo J, Tang M, Huang J, He BC, Gao JL, Chen L, Zuo GW, Zhang W, Luo Q, Shi Q, Zhang BQ, Bi Y, Luo X, Jiang W, Su Y, Shen J, Kim SH, Huang E, Gao Y, Zhou JZ, Yang K, Luu HH, Pan X, Haydon RC, Deng ZL, He TC (2010) TGFb/BMP Type I Receptors ALK1 and ALK2 Are Essential for BMP9-Induced Osteogenic Signaling in Mesenchymal Stem Cells. Journal of Biological Chemistry 285(38): 29588–29598 PMID: 20628059

Zhang W, Deng ZL, Chen L, Zuo GW, Luo Q, Shi Q, Zhang BQ, Wagner ER, Rastegar F, Kim SH, Jiang W, Shen J, Huang E, Gao Y, Gao JL, Zhou JZ, Luo J, Huang J, Luo X, Bi Y, Su Y, Yang K, Liu H, Luu HH, Haydon RC, He TC, He BC (2010) Retinoic Acids Potentiate BMP9-Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells. PLoS ONE 5(7): e11917

Chen L, Jiang W, Huang J, He BC, Zuo GW, Zhang W, Luo Q, Shi Q, Zhang BQ, Wagner ER, Luo J, Tang M, Wietholt C, Luo X, Bi Y, Su Y, Liu B, Kim SH, He CJ, Hu Y, Shen J, Rastegar F, Huang E, Gao Y, Gao JL, Zhou JZ, Reid RR, Luu HH, Haydon RC, He TC, Deng ZL (2010) Insulin-like Growth Factor 2 (IGF2) Potentiates BMP9-induced Osteogenic Differentiation of Mesenchymal Stem Cells and Bone Formation. Journal of Bone and Mineral Research 25(11): 2447-2459 PMID: 20499340 [Evaluated by Faculty of 1000, 06 Dec 2010. F1000.com/6670956]

He BC, Chen L, Zuo GW, Zhang W, Bi Y, Huang J, Wang Y, Jiang W, Luo Q, Shi Q, Zhang BQ, Liu B, Lei X, Luo J, Luo X, Wagner ER, Kim SH, He CJ, Hu Y, Shen J, Zhou Q, Rastegar F, Deng ZL, Luu HH, He TC, Haydon RC (2010) Synergistic anti-tumor effect of the activated PPARg and retinoid receptors on human osteosarcoma. Clinical Cancer Research 16(8); 2235–2245

Tang N, Song WX, Luo J, Luo X, Chen J, Sharff KA, Bi Y, He BC, Huang JY, Zhu GH, Su YX, Jiang W, Tang M, He Y, Wang Y, Chen L, Zuo GW, Shen J, Pan X, Reid RR, Luu HH, Haydon RC, He TC: (2009) BMP9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/b-catenin signaling. Journal of Cellular and Molecular Medicine 13 (8B):2448-2464

Sharff KA, Song WX, Luo X, Tang N, Luo J, Chen J, Bi Y, He BC, Huang J, Li X, Jiang W, Zhu GH, Su Y, He Y, Shen J, Wang Y, Chen L, Zuo GW, Liu B, Pan X, Reid RR, Luu HH, Haydon RC, He TC: (2009) Hey1 Basic Helix-Loop-Helix (bHLH) Protein Plays an Important Role in Mediating BMP9 Induced Osteogenic Differentiation of Mesenchymal Progenitor Cells. Journal of Biological Chemistry 284(1):649-659

Kang Q, Song WX, Luo Q, Tang N, Luo J, Luo X, Chen J, Bi Y, He BC, Park JK, Jiang W, Tang Y, Huang J, Su Y, Zhu GH, He Y, Yin H, Hu Z, Wang Y, Chen L, Zuo GW, Pan X, Shen J, Vokes T, Reid RR, Haydon RC, Luu HH, He TC: (2009) A Comprehensive Analysis of the Dual Roles of BMPs in Regulating Adipogenic and Osteogenic Differentiation of Mesenchymal Progenitor Cells. Stem Cells and Development 18(4): 545-559

Luo X, Chen J, Song WX, Tang N, Luo J, Deng ZL, Sharff KA, He G, Bi Y, He BC, Bennett E, Huang J, Kang Q, Jiang W, Su Y, Zhu GH, Yin H, He Y, Wang Y, Souris JS, Chen L, Zuo GW, Montag AG, Reid RR, Haydon RC, Luu HH, He TC: (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Laboratory Investigation 88(12):1264-1277

Luo J, Deng ZL, Luo X, Tang N, Song WX, Chen J, Sharff KA, Luu HH, Haydon RC, Kinzler KW, Vogelstein B, He TC: (2007) A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nature Protocols 2(5): 1236-1247

Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC: (2006) CCN1/Cyr61 is regulated by canonical Wnt signal and plays an important role in Wnt3A-induced early osteogenic differentiation. Molecular and Cellular Biology 26(8): 2955–2964

Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, Montag AG, Haydon RC, He TC: (2004) Connective Tissue Growth Factor (CTGF) is regulated by Wnt and BMP signaling in osteoblast differentiation of mesenchymal stem cells. Journal of Biological Chemistry 279 (53): 55958-55968

Kang Q, Sun MH, Cheng H, Peng Y, Montag AG, Deyrup AT, Jiang W, Luu HH, Luo J, Szatkowski JP, Vanichakarn P, Park JY, Li Y, Haydon RC, He TC: (2004) Characterization of the distinct orthotopic bone forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Therapy 11 (17): 1312–1320

Peng Y, Kang Q, Luo Q, Jiang W, Si W, Liu BA, Luu HH, Park JK, Li X, Luo J, Montag AG, Haydon RC, He TC: (2004) Id Helix-Loop-Helix Proteins Mediate BMP-induced Osteoblast Differentiation of Mesenchymal Stem Cells. Journal of Biological Chemistry 279(31): 32941-32949

Haydon RC, Zhou L, Feng T, Breyer B, Cheng H, Jiang W, Ishikawa A, Peabody T, Montag A, Simon MA, He TC: (2002) Nuclear receptor agonists as potential differentiation therapy agents for human osteosarcoma. Clinical Cancer Research 8: 1288-1294

He TC, Chan TA, Vogelstein B, Kinzler KW: (1999) PPAR delta is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell 99:335-345

He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW: (1998) Identification of c-Myc as a target of the APC pathway. Science, 281:1509-1512

He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B: (1998) A simplified system for generating recombinant adenoviruses. Proceedings of National Academy of Sciences USA 95:2509-2514

Faculty and Research

Programs

Cancer Biology

Immunology

Microbiology

Molecular Metabolism
and Nutrition

Molecular Pathogenesis and
Molecular Medicine