Molecular Biology Faculty
Yibin Kang
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 (609) 258-8834 |
 Lewis Thomas Lab, 255 |
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Lab (609) 258-9120 |
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Faculty Assistant
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Amanda Denzer-King
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(609) 258-6224 |
Research Focus
Molecular Mechanisms of Cancer Metastasis
The difference between life and death for most cancer patients hinges on the degree of spread, or metastasis, of their tumors. Therefore, a better molecular understanding of cancer metastasis holds significant promise for reducing mortality and morbidity from cancer. The central theme of our research is a multidisciplinary and integrative approach to the analysis of the molecular basis of cancer metastasis, combining molecular biology and genomics tools with animal models and advanced in vivo imaging technologies. We focus on the identification of metastasis genes and functional characterization of their involvement in tumor-stromal interactions during the formation of metastasis in different organs. We are also interested in regulators of mammary gland development and early oncogenic events that may have significant impact on tumor progression and metastasis.
Identification of novel metastasis genes through integrative genomics
Discovering metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics. We use two complementary approaches to harness the power of comprehensive profiling technologies, including genomics, proteomics and metabolomics, for the identification and validation of novel metastasis genes and pathways. Using a large collection of mouse models of cancer metastasis available in our laboratory, we identify candidate metastasis genes by genomic profiling of highly metastatic cells derived after in vivo selection. Functional characterization of these genes revealed the novel activities of several developmentally conserved pathways, including the EGFR, TGFb, and Notch pathways, in mediating tumor-stromal interactions essential for the formation of metastasis in vital organs such as bone, lung and brain. Importantly, pharmaceutical inhibitors against these signaling pathways are highly effective in reducing the development of metastasis, suggesting novel avenues for clinical management of metastatic cancer. We also developed integrative genomics strategies to utilize available clinical genomic profiling and sequencing data of human cancer to identify genetic alterations with functional impact on cancer metastasis. Using this approach, we identified Metadherin (MTDH) as a dual-functional gene that promotes metastasis and broad-spectrum chemoresistance of breast cancers. Ongoing studies in the lab are currently characterizing MTDH and additional candidate metastasis genes.
Molecular characterization of tumor stromal interactions in metastasis
It has become well-recognized that metastatic cancer cells do not act autonomously when they escape from the primary tumor and establish colonies at different organs. Rather, intricate interactions between tumor cells and their stromal microenvironment play an essential role in the pathogenesis of metastasis. Our laboratory uses a series of in vitro and in vivo models systems to dissect the molecular cross-talks between tumor cells and resident stromal cells. Advanced in vivo imaging technologies are being developed in the lab to analyze the signaling pathway dynamics and cellular interactions that occur at real time during the development and treatment of metastatic diseases. Such studies are crucial for the development of highly effective therapeutics against metastatic cancer.
The role of mammary gland stem cells in development and breast cancer
Although it was initially believed that metastasis capacity is acquired late during tumor progression, substantial evidence suggests that different early transformation events may set the resulting tumors on distinct paths towards either aggressive metastasis or slow progression. In recent years, the intriguing link between mammary stem cells (MaSCs) and breast cancer stem cells has generated tremendous interest due to its important implications in breast cancer etiology and therapeutics. Identifying the cellular origin of breast cancer will not only aid in understanding the early events that drive breast carcinogenesis, but will also yield critical insights to help understand the different tendencies of metastasis in different subtypes of breast cancer. In order to facilitate the study of MaSCs during tumorigenesis and metastasis, we recently developed a mouse model in which MaSCs can be detected by MaSC-specific expression of luciferase in the mammary epithelium. Using this model system, we will now investigating the regulation of MaSCs by canonical stem cell signaling pathways and breast cancer oncogenes, test the susceptibility of MaSCs, progenitor cells and differentiated cells to transformation, and study how the tumorigenic and/or metastatic potential of the resulting tumors are influenced by their cellular origin.
miRNAs and ncRNAs as regulators of tumor progression
miRNAs and other non-coding RNAs (ncRNAs) have emerge in recent years as important regulators of critical physiological and pathological processes. We recently discovered the miR-200 family of miRNAs as important regulators of epithelial-mesenchymal transition, which is believed to be the initial step of metastasis that enables the migration and invasion of tumor cells. We are using xenograft and transgenic mouse models to investigate the function of EMT-related miRNAs. Similar research strategy is being applied to identify and characterize other miRNAs and ncRNAs that may play a crucial role in different stage of tumor progression.
Selected Publications
Kang Y, Pantel K. (2013) Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell. 23: 573-81. Pubmed
Zheng H, Kang Y. (2013) Multilayer control of the EMT master regulators. Oncogene. [Epub ahead of print]
Smith HA, Kang Y. (2013) The metastasis-promoting roles of tumor-associated immune cells. J Mol Med (Berl). 91: 411-29. Pubmed
Ren G, Kang Y. (2013) A one-two punch of miR-126/126* against metastasis. Nat Cell Biol. 15: 231-3. Pubmed
Fang W, Wei Y, Kang Y, Landweber LF. (2012) Detection of a common chimeric transcript between human chromosomes 7 and 16. Biol Direct. 7: 49. Pubmed
Ell B, Kang Y. (2012) SnapShot: bone metastasis. Cell. 151: 690-690. Pubmed
Chakrabarti R, Hwang J, Andres Blanco M [...] Kang Y. (2012) Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol. 14: 1212-22. Pubmed
Chakrabarti R, Wei Y, Romano RA, DeCoste C, Kang Y, Sinha S. (2012) Elf5 regulates mammary gland stem/progenitor cell fate by influencing notch signaling. Stem Cells. 30: 1496-508. Pubmed
Blanco MA, Leroy G, Khan Z, Alečković M, Zee BM, Garcia BA, Kang Y. (2012) Global secretome analysis identifies novel mediators of bone metastasis. Cell Res. 22: 1339-1355. Pubmed
Koh BI, Kang Y. (2012) The pro-metastatic role of bone marrow-derived cells: a focus on MSCs and regulatory T cells. EMBO Rep. 13: 412-422. PubMed
Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Lu X, Haffty BG, Pantel K, Massagué J, Kang Y. (2011) VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell. 20: 701-714. PubMed
Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celià-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y, Wei Y, Hu G, Garcia BA, Ragoussis J, Amadori D, Harris AL, Kang Y. (2011) Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med. 17: 1101-1108. PubMed
Lu X, Kang Y. (2011) Cell fusion hypothesis of the cancer stem cell. Adv Exp Med Biol. 714: 129-140. PubMed
Blanco MA, Aleckovic M, Hua Y, Li T, Wei Y, Xu Z, Cristea IM, Kang Y. (2011) Identification of Staphylococcal nuclease domain containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions. J Biol Chem. 286: 19982-19992. PubMed
Blanco MA, Kang Y. (2011) Signaling pathways in breast cancer metastasis - novel insights from functional genomics. Breast Cancer Res. 13: 206. PubMed
Sethi N, Dai X, Winter CG, Kang Y. (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell. 19: 192-205. PubMed
Tiede B, Kang Y. (2011) From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Res. 21: 245-257. PubMed
Lu X, Kang Y. (2010) Hypoxia and hypoxia-inducible factors (HIFs): master regulators of metastasis. Clin Cancer Res. 16: 5928-5935. PubMed
Sethi N, Yan Y, Quek D, Schupbach T, Kang Y. (2010) Rabconnectin-3 is a functional regulator of mammalian notch signaling. J Biol Chem. 285: 34757-34764. PubMed
Sethi N, Kang Y. (2010) Dysregulation of developmental pathways in bone metastasis. Bone. 48: 16-22. PubMed
Lu X, Lu X, Kang Y. (2010) Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement. Cell Res. 20: 1012-1022. PubMed
Lu X, Yan CH, Yuan M, Wei Y, Hu G, Kang Y. (2010) In vivo dynamics and distinct functions of hypoxia in primary tumor growth and organotropic metastasis of breast cancer. Cancer Res. 70: 3905-3914. PubMed
Korpal M, Kang Y. (2010) Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. Eur J Cancer. 46: 1232-1240. PubMed
Lu X, Bennet B, Mu E, Rabinowitz J, Kang Y. (2010) Metabolomic changes accompanying transformation and acquisition of metastatic potential in a syngeneic mouse mammary tumor model. J Biol Chem. 285: 9317-9321. PubMed
Lu X, Kang Y. (2009) Epidermal growth factor signalling and bone metastasis. Br J Cancer. 102: 457-461. PubMed
Tiede BJ, Owens LA, Li F, Decoste C, Kang Y. (2009) A novel mouse model for non-invasive single marker tracking of mammary stem cells in vivo reveals stem cell dynamics throughout pregnancy. PLoS One. 4: e8035. PubMed
Lu X, Kang Y. (2009) Metalloproteinases and osteoblast EGFR signaling in osteolytic bone metastasis of breast cancer. Cell Cycle. 8: 3804-3805. PubMed
Lu X, Kang Y. (2009) Cell fusion as a hidden force in tumor progression. Cancer Res. 69: 8536-8539. PubMed
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. 284: 29087-29096. PubMed
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
