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Yibin Kang

Molecular Mechanisms of Cancer Metastasis

Metastasis, the spread of cancer cells from the primary tumor to distant organs, is the most dreadful development of neoplastic diseases. Although metastasis contributes to over 90% of human cancer mortality, the molecular mechanism of this process remains largely unknown. Our laboratory applies a multidisciplinary approach to analyze the molecular basis of cancer metastasis, combining molecular biology and genomics tools with animal models and advanced in vivo imaging technologies.

Identification and functional characterization of tissue-specific metastasis genes

Each type of cancer has a specific pattern of metastatic distributions. For example, breast cancer metastases can emerge in a variety of organs including bone, lung, lymph node and brain. In contrast, colorectal cancer frequently metastasizes to liver but rarely to bone. What determines the metastasis tissue tropism at the molecular level still remains a daunting challenge to cancer biologists. We have previously established a functional genomics strategy to identify tissue-specific metastasis genes. Human cancer cells were injected into the systemic blood circulation of immunodeficient mice. After the emergence of metastases in different target organs, sub-population of tumor cells with different metastatic ability and tissue-tropism were isolated. Candidate tissue-specific metastasis genes were identified by genomic profiling of these cells. Using this approach, we identified a breast cancer bone metastasis gene profile which contains known metastasis mediators such as the chemokine receptor CXCR4, as well as many genes that had not been implicated in metastasis previously. These genes regulate cell shape and migration, interactions with extracellular matrix and stroma, angiogenesis, and bone metabolism. Subsequent functional testing and clinical correlation studies validated the importance of these genes in human breast cancer bone metastasis. We are now applying similar strategies to analyze other types of cancer and other metastasis tissue tropisms. Using a series of in vivo and in vitro functional assays, candidate metastasis genes will be characterized for their roles in the multi-step metastasis cascade. We are also investigating the genetic and epigenetic events that lead to the aberrant expression of metastasis genes in highly metastatic cells. The ultimate goal of this line of research is to enable targeted therapeutics against the metastatic spread of cancer

Molecular network of tumor-stroma interactions during metastasis

The complex, dynamic interactions between tumor cells and the surrounding host microenvironment play a key role in promoting metastatic progression. To thrive in a secondary organ, cancer cells often utilize or alter the normal physiological functions of stroma cells. On the other hand, stroma microenvionment not only serves as a passive soil for the seeding and growth of metastatic cells, but also plays an active role in influencing the metastatic behavior of tumor cells. For example, bone matrix has abundant storage of cytokine TGFb, which has a profound growth inhibitory effect on normal epithelial cells and early stage tumor cells. However, this growth inhibitory effect is often selectively lost during tumor progression, and late stage breast cancer cells instead acquire the ability to respond to TGFb with enhanced metastasis potential. The release of TGFb from bone matrix during osteolytic bone metastasis activates the transcription of two bone metastasis genes, IL11 and CTGF, in cancer cells, further enhancing their metastatic behavior. One focus of our laboratory is to study the influence of growth factors or cytokines released from metastatic cancer cell on the cellular behaviors of stroma cells. With the establishment of a comprehensive inventory of metastasis genes, we will use bioinformatics tools to identify common signaling and transcriptional regulation pathways that influence metastasis gene functions. The role of these pathways in the tumor-stroma crosstalk during metastasis will be investigated. Delineation of the molecular interaction network between metastatic tumor cells and the surrounding target organ microenvironment will provide new insights about how metastatic growth is initiated and maintained.

Selected Publications

Hu G, Wei Y, Kang Y. (2009) The multifaceted role of MTDH/AEG-1 in cancer progression. Clin Cancer Res. 15: 5615-5620. PubMed

Lu X, Kang Y. (2009) Chemokine (C-C Motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J Biol Chem. [Epub ahead of print]

Hu G, Kang Y, Wang XF. (2009) From breast to the brain: Unraveling the puzzle of metastasis organotropism. J Mol Cell Biol. 1: 3-5. PubMed

Lu X, Wang Q, Hu G, Van Poznak C, Fleisher M, Reiss M, Massagué J, Kang Y. (2009) ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev. 23: 1882-1894. PubMed

Korpal M, Yan J, Lu X, Xu S, Lerit DA, Kang Y. (2009) Imaging transforming growth factor-beta signaling dynamics and therapeutic response in breast cancer bone metastasis. Nat Med. 15: 960-966. PubMed

Kang Y. (2009) Analysis of cancer stem cell metastasis in xenograft animal models. Methods Mol Biol. 568: 7-19. PubMed

Wei Y, Hu G, Kang Y. (2009) Metadherin as a link between metastasis and chemoresistance. Cell Cycle. 8: 2132-2133. PubMed

Lu X, Kang Y. (2009) Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc Natl Acad Sci. 106: 9385-9390. PubMed

Korpal M, Kang Y. (2009) The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol. 5: 115-119. PubMed

Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, Reiss M, Au JL, Haffty BG, Kang Y. (2009) MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 15: 9-20. PubMed

Korpal M, Lee ES, Hu G, Kang Y. (2008) The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 283: 14910-14914. PubMed

Zhu J, Jia X, Xiao G, Kang Y, Partridge NC, Qin L. (2007) EGF-like ligands stimulate osteoclastogenesis by regulating expression of osteoclast regulatory factors by osteoblasts: Implications for osteolytic bone metastases. J Biol Chem 282: 26656-26664. PubMed

Lu X, Kang Y. (2007) Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia 12: 153-162. PubMed

Kang Y. (2007) New tricks against an old foe: molecular dissection of metastasis tissue tropism in breast cancer. Breast Dis 26: 129-138. PubMed

Li F, Tiede B, Massague J, Kang Y. (2006) Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 17: 3-14. PubMed

Kang Y. (2006) Pro-metastasis function of TGFbeta mediated by the smad pathway. J Cell Biochem 98: 1380-1390. PubMed

Gupta GP, Minn AJ, Kang Y, Siegel PM, Serganova I, Cordon-Cardo C, Olshen AB, Gerald WL, Massague J. (2005) Identifying Site-specific Metastasis Genes and Functions. Cold Spring Harb Symp Quant Biol 70: 149-158. PubMed

Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M, Ponomarev V, Gerald WL, Blasberg R, Massague J. (2005) Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest 115: 44-55.  PubMed

Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen C, Manova-Todorava K, Blasberg R, Gerald WL, Massagué J. (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci USA 102: 13909-13914. PubMed

Kang Y. (2005) Functional genomic analysis of cancer metastasis: biologic insights and clinical implications. Expert Rev Mol Diagn 5: 385-395. PubMed

Kang Y, Massague J. (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118: 277-279. PubMed

Bodem J, Kang Y, Flugel RM. (2004) Comparative functional characterization of the feline foamy virus transactivator reveals its species specificity. Virology 318: 32-36. PubMed

Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J. (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3: 537-549. PubMed

Kang Y, Chen CR, Massague J. (2003) A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell 11: 915-926. PubMed

Xu L, Kang Y, Col S, Massague J. (2002). Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol Cell 10: 271-282. PubMed

Wiegand HL, Coburn GA, Zeng Y, Kang Y, Bogerd HP, Cullen BR. (2002) Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes. Mol Cell Biol 22: 245-256. PubMed

Ho DN, Coburn GA, Kang Y, Cullen BR, Georgiadis MM. (2002) The crystal structure and mutational analysis of a novel RNA-binding domain found in the human Tap nuclear mRNA export factor. Proc Natl Acad Sci USA 99: 1888-1893. PubMed

Chen CR, Kang Y, Siegel PM, Massague J. (2002) E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110: 19-32. PubMed

Coburn GA, Wiegand HL, Kang Y, Ho DN, Georgiadis MM, Cullen BR. (2001) Using viral species specificity to define a critical protein/RNA interaction surface. Genes Dev 15: 1194-1205. PubMed

Chen CR, Kang Y, Massague J. (2001) Defective repression of c-myc in breast cancer cells: A loss at the core of the transforming growth factor beta growth arrest program. Proc Natl Acad Sci USA 98: 992-999. PubMed

Neufeld KL, Nix DA, Bogerd H, Kang Y, Beckerle MC, Cullen BR, White RL. (2000) Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm. Proc Natl Acad Sci USA 97: 12085-12090. PubMed

Kang Y, Bogerd HP, Cullen BR. (2000) Analysis of cellular factors that mediate nuclear export of RNAs bearing the Mason-Pfizer monkey virus constitutive transport element. J Virol 74: 5863-5871. PubMed

Truant R, Kang Y, Cullen BR. (1999) The human tap nuclear RNA export factor contains a novel transportin-dependent nuclear localization signal that lacks nuclear export signal function. J Biol Chem 274: 32167-32171. PubMed

Kang Y, Cullen BR. (1999) The human Tap protein is a nuclear mRNA export factor that contains novel RNA-binding and nucleocytoplasmic transport sequences. Genes Dev 13: 1126-1139. PubMed

Kang Y, Bogerd HP, Yang J, Cullen BR. (1999) Analysis of the RNA binding specificity of the human tap protein, a constitutive transport element-specific nuclear RNA export factor. Virology 262: 200-209. PubMed

Kang Y, Cullen BR. (1998) Derivation and functional characterization of a consensus DNA binding sequence for the tas transcriptional activator of simian foamy virus type 1. J Virol 72: 5502-5509. PubMed

Kang Y, Blair WS, Cullen BR. (1998) Identification and functional characterization of a high-affinity Bel-1 DNA binding site located in the human foamy virus internal promoter. J Virol 72: 504-511.  PubMed