He, Tong-Chuan, M.D., Ph.D.

Deregulation of Wnt/beta-catenin Signaling in Human Cancer; Molecular Biology of Bone and Soft Tissue Tumors; Gene Therapy.

Research Summary

The Molecular Oncology Laboratory primarily focuses on the following areas: 

(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

Ni Tang, Wen-Xin Song, Jinyong Luo,  Xiaoji Luo, Jin Chen, Katie A.Sharff, Yang Bi, Bai-Cheng He, Jia-Yi Huang, Gao-Hui Zhu, Yu-Xi Su, Wei Jiang, Min Tang, Yun He,  Yi Wang, Liang Chen, Guo-Wei Zuo, Jikun Shen, Xiaochuan Pan, Russell R. Reid, Hue H. Luu, Rex C. Haydon, and Tong-Chuan He:  (2009) BMP9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signaling. Journal of Cellular and Molecular Medicine [in press].  

Katie A. Sharff*, Wen-Xin Song*, Xiaoji Luo, Ni Tang, Jinyong Luo, Jin Chen, Yang Bi, Bai-Cheng He, Jiayi Huang, Xinmin Li, Wei Jiang, Gao-Hui Zhu, Yuxi Su, Yun He, Jikun Shen, Yi Wang, Liang Chen, Guo-Wei Zuo, Bo Liu, Xiaochuan Pan, Russell R. Reid, Hue H. Luu, Rex C. Haydon#, and Tong-Chuan He#: (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 (* equal contributions; # co-corresponding authors).

Quan Kang, Wen-Xin Song, Qing Luo, Ni Tang, Jinyong Luo, Xiaoji Luo, Jin Chen, Yang Bi, Bai-Cheng He, Jong Kyung Park, Wei Jiang, Yi Tang, Jiayi Huang, Yuxi Su, Gao-Hui Zhu, Yun He, Hong Yin, Zhenming Hu, Yi Wang, Liang Chen, Guowei Zuo, Xiaochuan Pan, Jikun Shen, Tamara Vokes, Russell Reid, Rex C. Haydon, Hue H. Luu, and Tong-Chuan He: (2009) A Comprehensive Analysis of the Dual Roles of BMPs in Regulating Adipogenic and Osteogenic Differentiation of Mesenchymal Progenitor Cells.  Stem Cells and Development  [in press].

Xiaoji Luo*, Jin Chen*, Wen-Xin Song, Ni Tang, Jinyong Luo, Zhong-Liang Deng, Katie A. Sharff, Gary He, Yang Bi, Bai-Cheng He, Erwin Bennett, Jiayi Huang, Quan Kang, Wei Jiang, Yuxi Su, Gao-Hui Zhu, Hong Yin, Yun He, Yi Wang, Jeffrey S. Souris, Liang Chen, Guo-Wei Zuo, Anthony G. Montag, Russell Reid, Rex C. Haydon, Hue H. Luu,# and Tong-Chuan He#:  (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects.  Laboratory Investigation  88(12):1264-1277 (* equal contributions; # co-corresponding authors).
Ni Tang, Wen-Xin Song, Jinyong Luo, Rex C. Haydon and Tong-Chuan He: (2008) Osteosarcoma Development and Stem Cell Differentiation.  Clinical Orthopaedics and Related Research  466: 2114–2130.
Zhong-Liang Deng, Katie A. Sharff, Ni Tang, Wen-Xin Song, Jinyong Luo, Xiaoji Luo, Jin Chen, Erwin Bennett, Russell Reid, David Manning, Anita Xue, Anthony G. Montag, Hue H. Luu, Rex C. Haydon and Tong-Chuan He: (2008) Regulation of osteogenic differentiation during skeletal development.  Frontiers in Bioscience  13: 2001-2021.

Xiaoji Luo, Katie Sharff, Rex C. Haydon, Tong-Chuan He, and Hue H. Luu: (2008) S100A6 expression and function in osteosarcoma.  Clinical Orthopaedics and Related Research   466: 2060–2070.

Jinyong Luo, Zhong-Liang Deng, Xiaoji Luo, Ni Tang, Wen-Xin Song, Jin Chen, Katie A. Sharff, Hue H. Luu, Rex C. Haydon, Kenneth W. Kinzler, Bert Vogelstein, and Tong-Chuan He: (2007) A protocol for rapid generation of recombinant adenoviruses using the AdEasy system.  Nature Protocols  2(5): 1236-1247.

Hue H. Luu, Wen-Xin Song, Xiaoji Luo, David Manning, Jinyong Luo, Zhongliang Deng, Katie Sharff, Anthony G. Montag, Rex C. Haydon and Tong-Chuan He: (2007) The Distinct Roles of Bone Morphogenetic Proteins in Osteogenic Differentiation of Mesenchymal Stem Cells.  Journal of Orthopaedic Research  25(5): 665-677.

Jinyong Luo, Jin Chen, Zhong-Liang Deng, Xiaoji Luo, Wen-Xin Song, Katie A. Sharff, Ni Tang, Rex C. Haydon, Hue H. Luu, and Tong-Chuan He: (2007) Wnt signaling and human diseases:  what are the therapeutic implications?  Laboratory Investigation  87: 97–103.

Rex C. Haydon, Hue H. Luu, and Tong-Chuan He: (2007) Osteoblastic differentiation and osteosarcoma: a new perspective on oncogenesis.  Clinical Orthopaedics and Related Research  454:237-246.

Qing Luo, Quan Kang, Wen-Xin Song, Hue H. Luu, Xiaoji Luo, Naili An, Jinyong Luo, Zhong-Liang Deng, Wei Jiang, Hong Yin, Jin Chen, Katie Sharff , Ni Tang, Erwin Bennett, Rex C. Haydon, and Tong-Chuan He: (2007) Selection and validation of optimal siRNA target sites for RNAi-mediated gene silencing.  Gene  395(1-2): 160-169.

Weike Si, Quan Kang, Hue H. Luu, Jong Kyung Park, Qing Luo, Wen-Xin Song, Wei Jiang, Xiaoji Luo, Xinmin Li, Hong Yin, Anthony G. Montag, Rex C. Haydon, and Tong-Chuan He: (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.
Hue H. Luu, Quan Kang, Jong Kyung Park, Weike Si, Qing Luo, Wei Jiang, Hong Yin, Anthony G. Montag, Michael A. Simon, Terrance D. Peabody, Rex C. Haydon, Carrie W. Rinker-Schaeffer, and Tong-Chuan He:   (2005) An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis.  Clinical & Experimental Metastasis   22 (4): 319-329.

Jeffrey Luo, Michael H. Sun, Quan Kang, Ying Peng, Wei Jiang, Hue H. Luu, Qing Luo, Jae Yoon Park, Yien Li, Rex C. Haydon, and Tong-Chuan He: (2005) Gene Therapy for Bone Regeneration.  Current Gene Therapy  5(2): 167-179.

Hue H. Luu, Lan Zhou, Rex C. Haydon, Andrea T. Deyrup, Anthony G. Montag, Dezheng Huo, Robert Heck, Claus W. Heizmann, Terrance Peabody, Michael A. Simon, and Tong-Chuan He:  (2005) Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma.  Cancer Letters  229 (1): 135-148.