FocusMolecular 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.
Yibin Kang (康毅滨) is a Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University. He graduated with a bachelor's degree from Fudan University in Shanghai in 1995. After completing his graduate study at Duke in 2000, Dr. Kang became an Irvington Institute postdoctoral fellow with Dr. Joan Massagué at the Memorial Sloan-Kettering Cancer Center and pioneered a functional genomic approach to elucidate mechanism of breast cancer metastasis. Dr. Kang joined the faculty of Princeton University as an Assistant Professor of Molecular Biology in 2004. He was promoted to Associate Professor with tenure in 2010 and to Endowed Chair Full Professor in 2012.
Dr. Kang's research focuses on the molecular mechanisms of breast cancer metastasis. His 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. Dr. Kang has published over 100 original articles in leading journals including Cell, Cancer Cell, and Nature Medicine. His work discovered new genes that promote recurrence, metastasis and chemoresistance of breast cancer, delineated tumor-stromal interactions that are essential for metastatic growth, and identified novel regulators with dual functions in mammary gland cell fate determination and tumor progression. Dr. Kang's outstanding achievements have been recognized by many prestigious awards, including a Department of Defense Era of Hope Scholar Award and the 2011 Vicek Prize for Creative Promise in Biomedical Sciences, a prestigious award honoring foreign-born artists and scientists who have demonstrated exceptional creativity and originality in the early stages of their careers in the United States. Dr. Kang is also the recipient of the 2012 AACR Award for Outstanding Achievements in Cancer Research, the Fuller Albright Award of the American Society of Bone and Mineral Research, and the 2014 Josh Fidler Innovation in Metastasis Research Award from the Metastasis Research Society. Dr. Kang was a member of the Board of Directors of the Metastasis Research Society from 2008 to 2012. He was elected as the President of the society in 2014 and will serve his term from 2016 to 2018.
Honors & Awards
- Komen Scholar Award, Susan G. Komen Foundation
- Innovation Award, Department of Molecular Biology, Princeton University
- Duke Graduate School Few-Glasson Alumni Society, Duke University
- AACR Outstanding Investigator Award, American Association for Breast Cancer Research
- AACR Award for Outstanding Achievement in Cancer Research, American Association for Cancer Research
- Vilcek Prize for Creative Promise in Biomedical Science, Vilcek Foundation
- B.S., Genetics, Fudan University, Shanghai
- Ph.D., Genetics, Duke University, Durham, NC
- 1.Chen H, Zhan M, Liu J, Liu Z, Shen M, Yang F, Kang Y, Yin F, Li Z. Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction. J Med Chem. 2022;65(18):12188–12199. PMID: 36044768
- 1.Meng J, Jiang Y-Z, Zhao S, Tao Y, Zhang T, Wang X, Zhang Y, Sun K, Yuan M, Chen J, Wei Y, Lan X, Chen M, David C, Chang Z, Guo X, Pan D, Chen M, Shao Z-M, Kang Y, Zheng H. Tumor-derived Jagged1 promotes cancer progression through immune evasion. Cell Rep. 2022;38(10):110492. PMID: 35263601
- 1.Pérez-Núñez I, Rozalén C, Palomeque J, Sangrador I, Dalmau M, Comerma L, Hernández-Prat A, Casadevall D, Menendez S, Liu D, Shen M, Berenguer J, Ruiz I, Peña R, Montañés J, Albà M, Bonnin S, Ponomarenko J, Gomis R, Cejalvo J, Servitja S, Marzese D, Morey L, Voorwerk L, Arribas J, Bermejo B, Kok M, Pusztai L, Kang Y, Albanell J, Celià-Terrassa T. LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer. Nat Cancer. 2022;3(3):355–370. PMCID: 5391692
- 1.Kumar S, Nandi A, Singh S, Regulapati R, Li N, Tobias J, Siebel C, Blanco M, Klein-Szanto A, Lengner C, Welm A, Kang Y, Chakrabarti R. Author Correction: Dll1+ quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway. Nat Commun. 2022;13(1):3927. PMCID: PMC9262875
- 1.Shen M, Wei Y, Kim H, Wan L, Jiang Y-Z, Hang X, Raba M, Remiszewski S, Rowicki M, Wu C-G, Wu S, Zhang L, Lu X, Yuan M, Smith H, Zheng A, Bertino J, Jin J, Xing Y, Shao Z-M, Kang Y. Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis. Nat Cancer. 2022;3(1):43–59. PMCID: PMC8818087
- 1.Shen M, Smith H, Wei Y, Jiang Y-Z, Zhao S, Wang N, Rowicki M, Tang Y, Hang X, Wu S, Wan L, Shao Z-M, Kang Y. Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer. Nat Cancer. 2022;3(1):60–74. PMCID: PMC8818088
- 1.Spadazzi C, Mercatali L, Esposito M, Wei Y, Liverani C, De Vita A, Miserocchi G, Carretta E, Zanoni M, Cocchi C, Bongiovanni A, Recine F, Kang Y, Ibrahim T. Trefoil factor-1 upregulation in estrogen-receptor positive breast cancer correlates with an increased risk of bone metastasis. Bone. 2021;144:115775. PMID: 33249323
- 1.Esposito M, Fang C, Cook K, Park N, Wei Y, Spadazzi C, Bracha D, Gunaratna R, Laevsky G, DeCoste C, Slabodkin H, Brangwynne C, Cristea I, Kang Y. TGF-β-induced DACT1 biomolecular condensates repress Wnt signalling to promote bone metastasis. Nat Cell Biol. 2021;23(3):257–267. PMCID: PMC7970447
- 1.Kumar S, Nandi A, Singh S, Regulapati R, Li N, Tobias J, Siebel C, Blanco M, Klein-Szanto A, Lengner C, Welm A, Kang Y, Chakrabarti R. Dll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway. Nat Commun. 2021;12(1):432. PMCID: PMC7813834
- 1.Song K, Cai X, Dong Y, Wu H, Wei Y, Shankavaram U, Cui K, Lee Y, Zhu B, Bhattacharjee S, Wang B, Zhang K, Wen A, Wong S, Yu L, Xia L, Welm A, Bielenberg D, Camphausen K, Kang Y, Chen H. Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development. J Clin Invest. 2021;131(1). PMCID: PMC7773373
- 1.Shen M, Xie S, Rowicki M, Michel S, Wei Y, Hang X, Wan L, Lu X, Yuan M, Jin J, Jaschinski F, Zhou T, Klar R, Kang Y. Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis. Cancer Res. 2021;81(4):1014–1025. PMCID: PMC8026491
- 1.Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford H, Fuxe J, de Herreros A, Goodall G, Hadjantonakis A-K, Huang R, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore G, Mani S, Massagué J, Mayor R, McClay D, Mostov K, Newgreen D, Nieto A, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler M, Takahashi Y, Takeichi M, Theveneau E, Thiery J, Thompson E, Weinberg R, Williams E, Xing J, Zhou B, Sheng G, EMT International Association (TEMTIA). Author Correction: Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2021;22(12):834. PMCID: PMC8604719
- 1.Yang M, Hu X, Bao W, Zhang X, Lin Y, Stanton S, Haffty B, Hu W, Kang Y, Wei S, Zhang L. Changing trends and disparities in 5-year overall survival of women with invasive breast cancer in the United States, 1975-2015. Am J Cancer Res. 2021;11(6):3201–3211. PMCID: PMC8263668
- 1.Vrla G, Esposito M, Zhang C, Kang Y, Seyedsayamdost M, Gitai Z. Cytotoxic alkyl-quinolones mediate surface-induced virulence in Pseudomonas aeruginosa. PLoS Pathog. 2020;16(9):e1008867. PMCID: PMC7515202
- 1.Pham K, Huynh D, Le L, Delitto D, Yang L, Huang J, Kang Y, Steinberg M, Li J, Zhang L, Liu D, Tang M-S, Liu C, Wang H. E-cigarette promotes breast carcinoma progression and lung metastasis: Macrophage-tumor cells crosstalk and the role of CCL5 and VCAM-1. Cancer Lett. 2020;491:132–145. PMCID: PMC9703643
- 1.Li W, Shen M, Jiang Y-Z, Zhang R, Zheng H, Wei Y, Shao Z-M, Kang Y. Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2. Genes Dev. 2020;34(19-20):1310–1315. PMCID: PMC7528704
- 1.Fan H, Wang X, Li W, Shen M, Wei Y, Zheng H, Kang Y. ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP. Genes Dev. 2020;34(19-20):1359–1372. PMCID: PMC7528707
- 1.Yau T, Kang Y-K, Kim T-Y, El-Khoueiry A, Santoro A, Sangro B, Melero I, Kudo M, Hou M-M, Matilla A, Tovoli F, Knox J, He A, El-Rayes B, Acosta-Rivera M, Lim H-Y, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020;6(11):e204564. PMCID: PMC7530824
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- 1.Satoh T, Kang Y-K, Chao Y, Ryu M-H, Kato K, Chung H, Chen J-S, Muro K, Kang W, Yeh K-H, Yoshikawa T, Oh S, Bai L-Y, Tamura T, Lee K-W, Hamamoto Y, Kim J, Chin K, Oh D-Y, Minashi K, Cho J, Tsuda M, Tanimoto M, Chen L-T, Boku N. Exploratory subgroup analysis of patients with prior trastuzumab use in the ATTRACTION-2 trial: a randomized phase III clinical trial investigating the efficacy and safety of nivolumab in patients with advanced gastric/gastroesophageal junction cancer. Gastric Cancer. 2020;23(1):143–153. PMCID: PMC6942596
- 1.Hoshino A, Kim H, Bojmar L, Gyan K, Cioffi M, Hernandez J, Zambirinis C, Rodrigues G, Molina H, Heissel S, Mark M, Steiner L, Benito-Martin A, Lucotti S, Di Giannatale A, Offer K, Nakajima M, Williams C, Nogués L, Vatter F, Hashimoto A, Davies A, Freitas D, Kenific C, Ararso Y, Buehring W, Lauritzen P, Ogitani Y, Sugiura K, Takahashi N, Alečković M, Bailey K, Jolissant J, Wang H, Harris A, Schaeffer M, García-Santos G, Posner Z, Balachandran V, Khakoo Y, Raju P, Scherz A, Sagi I, Scherz-Shouval R, Yarden Y, Oren M, Malladi M, Petriccione M, De Braganca K, Donzelli M, Fischer C, Vitolano S, Wright G, Ganshaw L, Marrano M, Ahmed A, DeStefano J, Danzer E, Roehrl M, Lacayo N, Vincent T, Weiser M, Brady M, Meyers P, Wexler L, Ambati S, Chou A, Slotkin E, Modak S, Roberts S, Basu E, Diolaiti D, Krantz B, Cardoso F, Simpson A, Berger M, Rudin C, Simeone D, Jain M, Ghajar C, Batra S, Stanger B, Bui J, Brown K, Rajasekhar V, Healey J, de Sousa M, Kramer K, Sheth S, Baisch J, Pascual V, Heaton T, La Quaglia M, Pisapia D, Schwartz R, Zhang H, Liu Y, Shukla A, Blavier L, DeClerck Y, LaBarge M, Bissell M, Caffrey T, Grandgenett P, Hollingsworth M, Bromberg J, Costa-Silva B, Peinado H, Kang Y, Garcia B, O’Reilly E, Kelsen D, Trippett T, Jones D, Matei I, Jarnagin W, Lyden D. Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers. Cell. 2020;182(4):1044–1061.e18. PMCID: PMC7522766
- 1.Yau T, Hsu C, Kim T-Y, Choo S-P, Kang Y-K, Hou M-M, Numata K, Yeo W, Chopra A, Ikeda M, Kuromatsu R, Moriguchi M, Chao Y, Zhao H, Anderson J, Cruz C, Kudo M. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis. J Hepatol. 2019;71(3):543–552. PMID: 31176752
- 1.Esposito M, Mondal N, Greco T, Wei Y, Spadazzi C, Lin S-C, Zheng H, Cheung C, Magnani J, Lin S-H, Cristea I, Sackstein R, Kang Y. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019;21(5):627–639. PMCID: PMC6556210
- 1.Lu S, Han Z, Hung M-C, Xu J, Xu Y, Zheng P, Zheng Z-M, Zou L, Li Z, Zheng L, Kang Y, Yang Y, He L, Liao C, Yu H, Yue Z, Liu S-L, Zheng H. Racial profiling harms science. Science. 2019;363(6433):1290–1292. PMID: 30898924
- 1.Celià-Terrassa T, Bastian C, Liu D, Ell B, Aiello N, Wei Y, Zamalloa J, Blanco A, Hang X, Kunisky D, Li W, Williams E, Rabitz H, Kang Y. Author Correction: Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat Commun. 2019;10(1):527. PMCID: PMC6349917
- 1.Shen M, Jiang Y-Z, Wei Y, Ell B, Sheng X, Esposito M, Kang J, Hang X, Zheng H, Rowicki M, Zhang L, Shih W, Celià-Terrassa T, Liu Y, Cristea I, Shao Z-M, Kang Y. Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling. Cancer Cell. 2019;35(1):64–80.e7. PMID: 30612941
- 1.Monsivais D, Peng J, Kang Y, Matzuk M. Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma. Proc Natl Acad Sci U S A. 2019;116(9):3883–3892. PMCID: PMC6397539
- 1.Zhang H, Brown R, Wei Y, Zhao P, Liu S, Liu X, Deng Y, Hu X, Zhang J, Gao X, Kang Y, Mercurio A, Goel H, Cheng C. CD44 splice isoform switching determines breast cancer stem cell state. Genes Dev. 2019;33(3-4):166–179. PMCID: PMC6362815
- 1.Zhuo W, Liu Y, Li S, Guo D, Sun Q, Jin J, Rao X, Li M, Sun M, Jiang M, Xu Y, Teng L, Jin Y, Si J, Liu W, Kang Y, Zhou T. Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS. Gastroenterology. 2019;156(3):676–691.e11. PMID: 30445010
- 1.Liverani C, De Vita A, Minardi S, Kang Y, Mercatali L, Amadori D, Bongiovanni A, La Manna F, Ibrahim T, Tasciotti E. A biomimetic 3D model of hypoxia-driven cancer progression. Sci Rep. 2019;9(1):12263. PMCID: PMC6706452
- 1.Zijlstra A, Von Lersner A, Yu D, Borrello L, Oudin M, Kang Y, Sahai E, Fingleton B, Stein U, Cox T, Price J, Kato Y, Welm A, Aguirre-Ghiso J, Board Members of the Metastasis Research Society. The importance of developing therapies targeting the biological spectrum of metastatic disease. Clin Exp Metastasis. 2019;36(4):305–309. PMCID: PMC8794535
- 1.Celià-Terrassa T, Bastian C, Liu D, Ell B, Aiello N, Wei Y, Zamalloa J, Blanco A, Hang X, Kunisky D, Li W, Williams E, Rabitz H, Kang Y. Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. Nat Commun. 2018;9(1):5005. PMCID: PMC6258667
- 1.Chakrabarti R, Celià-Terrassa T, Kumar S, Hang X, Wei Y, Choudhury A, Hwang J, Peng J, Nixon B, Grady J, DeCoste C, Gao J, van Es J, Li M, Aifantis I, Clevers H, Kang Y. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science. 2018;360(6396). PMCID: PMC7881440
- 1.Jin L, Chun J, Pan C, Kumar A, Zhang G, Ha Y, Li D, Alesi G, Kang Y, Zhou L, Yu W-M, Magliocca K, Khuri F, Qu C-K, Metallo C, Owonikoko T, Kang S. The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer. Mol Cell. 2018;69(1):87–99.e7. PMCID: PMC5777230