Nancy Du Lab
Exploring molecular mechanisms of cancer metastasis
Ninety percent of cancer patients do not die of locally confined cancer, but rather from cancer that has spread, leading to diminished function of vital organs. There is an urgent need to better understand drivers of cancer metastasis and to identify novel therapeutic targets.

We want to help patients through our research. The focus in Nancy Du laboratory is to understand the molecular mechanisms underlying metastasis. Our long-term goal is to develop therapeutic strategies to prevent metastatic tumor formation and inhibit metastatic tumor growth. We have developed novel model systems to study the in vivo effects of candidate genes in tumor progression. Major research areas include: identification and functional characterization of metastasis genes and non-coding RNAs, and pre-clinical evaluation of anti-tumor therapeutics.

In many human cancers, the gene that produces RHAMM is over-expressed, leading to too much RHAMM protein. While it is unclear whether RHAMM itself plays a causal role in tumor initiation or progression, we demonstrated that an alternative form of RHAMM, RHAMMB or RHAMMv3, promotes the growth of pancreatic tumors and their spread to lymph nodes and the liver. It was thought that pancreatic cancer metastasizes naturally to the liver simply because the two organs are next to each other in the abdomen. But in a seminal experiment, we identified RHAMMB as the first protein to promote liver-specific metastasis of pancreatic neuroendocrine tumors. In addition, we and others found that overexpression of RHAMM predicts poor survival in cancer patients.

Bcl-xL is another gene that is over-expressed in human cancers, including pancreatic cancer and breast cancer. This protein is normally present in the mitochondrial compartment of a cell, and has been known for its function in preventing a common, programmed form of cell death (apoptosis). When Bcl-xL is overexpressed in cancer, it helps cancer cells to survive. Several drugs have been developed to inhibit the anti-apoptotic function of Bcl-xL. Unfortunately, these drugs have limited therapeutic value in clinical trials by themselves. We demonstrated that in cancer, Bcl-xL travels to the nucleus to promote metastasis independent of its anti-apoptotic function. Our studies suggested a paradigm-shifting insight of Bcl-xL. This unexpected finding provides a possible explanation for why clinical trials using drugs to block anti-apoptosis roles of Bcl-xL have not been effective in halting cancer progression.

Dr. Yi-Chieh Nancy Du has been deeply attracted to science since she was in elementary school. She convinced her father to get her microscope, chemicals, beakers, and test tubes to do experiments at home. To pursue her passion in scientific discovery, Dr. Du gave up the opportunity of entering medical school, and joined Department of Life Science at National Tsing Hua University (NTHU), Taiwan. She received mentorship from Dr. Pien-Chien Huang, Dr. Tzong-Hsiung Hseu, and many other professors. She learned how to engineer protein mutations and purify proteins during her undergraduate research at NTHU and summer research at Yale University. This experience broadened Dr. Du’s perspective and made her want to stay in the lab day and night. She found out that the joy from doing research greatly balances out against the frustration and sometimes the loneliness.

After graduated with a bachelor's degree from NTHU, Dr. Du entered PhD program of State University of New York at Stony Brook. She was trained by Dr. Bruce Stillman at Cold Spring Harbor Laboratory. Dr. Stillman has made many significant achievements including the biochemical reconstitution with purified proteins of the complete replication of the SV40 DNA genome and the discovery of the Origin Recognition Complex (ORC). In Dr. Du’s graduate studies, she discovered a regulatory mechanism that coordinates cell proliferation with DNA replication and ribosome biogenesis using yeast (Du and Stillman, Cell, 2002).

As a result of her PhD work, Dr. Du developed interests in cancer research and became a postdoctoral fellow with Nobel Laureate Dr. Harold Varmus at Memorial Sloan Kettering Cancer Center. The most important work from her postdoctoral studies was to develop a mouse model, RIP-Tag; RIP-tva, to study metastasis (Du et al., PLoS Biology, 2007). Using a novel and innovative approach of employing somatic gene transfer system, this mouse model offers a unique opportunity to investigate molecular networks that drive the tumor progression to metastasis.

In her laboratory at Weill Cornell Medicine, Dr. Du and her team have expanded the scope from mouse models to human tissues and have been collaborating with other scientists and clinicians to better understand cancer metastasis. Dr. Du’s laboratory applies a multidisciplinary approach to analyze the molecular mechanism of metastasis, combining molecular biology and genomics tools with animal models and in vivo imaging technologies. Dr. Du’s achievements have been recognized by Scholar-in-Training Award from the American Association for Cancer Research, Career Development Award from Department of Defense, President's Council of Cornell Women Affinito-Stewart Award, and BCRP Breakthrough Award from Department of Defense.

Du, Y.-C. N. and Stillman, B. (2002). Yph1p, an ORC-interacting protein: potential links between cell proliferation control, DNA replication, and ribosome biogenesis. Cell, 109, 835-848.
Perspectives and Comments about this Paper:
  • Mitchell, A. (2002). DNA replication: a complex landing, Nature Reviews Molecular Biology, 3, 550.
  • LeBrasseur, N. (2002). Coordination of replication, Journal of Cell Biology, 158, 385.
  • Sadler, K. C. (2002). Ribosome assembly reawakens, Trends in Cell Biology, 12, 411.



Varmus, H., Pao, W., Politi, K., Podsypanina, K., and Du, Y.-C. N. (2005). Oncogenes come of age. Cold Spring Harbor Symposia on Quantitative Biology, 70, 1-9.



Du, Y.-C. N.*, Lewis, B., Hanahan, D., and Varmus, H. (2007). Assessing Tumor Progression Factors by Somatic Gene Transfer into a Mouse Model: Bcl-xL Promotes Islet Tumor Cell Invasion. PLoS Biology, 5, 2255-2269. (*corresponding author)
Research Highlights about this Paper:
  • Stevens, K. (2008). There is a virus going around. Nature Methods, 5, 6-7.



Podsypanina, K., Du, Y.-C. N., Jechlinger, M., Beverly L. J., Hambardzumyan, D., and Varmus, H. (2008). Seeding and propagation of untransformed mouse mammary cells in the lung. Science, 321, 1841-1844.
Preview about this Paper:
  • Weinberg, R.A. (2008). Leaving home early: reexamination of the canonical models of tumor progression. Cancer Cell, 14, 283-284.



Du, Y.-C. N.*, Klimstra, D., and Varmus, H. (2009). Conditional activation of PyMT in β cells induces irreversible benign β-cell hyperplasia but oncogene-dependent acinar cell carcinomas when activated in pancreatic progenitor cells. PLoS ONE, 4, e6932. (*corresponding author)



Reddy, J.P., Peddibhotla, S., Bu, W., Zhao, J., Haricharan, S., Du, Y.-C. N., Podsypanina, K., Rosen, J. M., Donehower, L. A., and Li, Y. (2010). ATM-dependent apoptosis and senescence are activated in somatic mammary cells following ErbB2-induced aberrant proliferation. PNAS, 107, 3728-3733.



Du, Y.-C. N.*, Chou, C.K., Klimstra, D., and Varmus, H. (2011). Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis. PNAS. 108, 16753-16758. (*corresponding author)



Tang, L.H., Contractor T., Klimstra, D., Du, Y.-C. N., Allen P.J., Brennan M.F., Levine A.J., Harris, C.R. (2012). Attenuation of the Rb pathway in pancreatic neuroendocrine tumors due to increased Cdk4/Cdk6. Clinical Cancer Research. 18, 4612-4620.



Choi, S., Chen, Z., Tang, L., Fang, Y., Shin, S., N., Panarelli, N., Chen, Y.T., Li, Y., Jiang, X. and Du, Y.-C. N.* (2016). Bcl-xL Promotes Metastasis Independent of its Anti-apoptotic Activity. Nature Communications. 7, Article number: 10384. (*corresponding author)



Yuan, Z., Claros, C.S., Suzuki, M., Maggi, E.C., Kaner, J.D., Kinstlinger, N., Gorecka, J., Quinn, T.J., Geha, R., Corn, A., Pastoriza, J., Jing, Q., Adem, A., Wu, H., Alemu, G., Du, Y.-C. N., Zheng, D., Greally, J.M., and Libutti, S.K. (2016). Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis, Oncotarget, PMID: 26871472.



Wang, D., Narula, N., Azzopardi, S., Smith, R.S., Nasar A., Altorki N.K., Mittal, V., Somwar, R., Stiles, B., Du, Y.-C. N.*. (2016) Expression of the Receptor for Hyaluronic Acid Mediated Motility (RHAMM) in Non-small Cell Lung Carcinoma and its Association with Metastasis. Oncotarget. PMID: 27220886. (*corresponding author)



Azzopardi, S., Pang, S., Klimstra, D., Du, Y.-C. N.*. (2016) p53 and p16Ink4a/p19Arf loss promote different pancreatic tumor types from PyMT-expressing progenitor cells. Neoplasia. Accepted. (*corresponding author)


Principal Investigator

Yi-Chieh Nancy Du

Postdoctoral Fellow

Yudan Chi


Research Technician

George Zhang


Student

Sharon Pang

Megan Wong

Samantha Li

Alumni
Name
Time In Lab
Journey After Lab

Anthony (Tony) Daniyan
2010
Memorial Sloan Kettering Cancer Center

Leigh Selesner
2010 - 2014
Temple University School of Medicine

Stephanie Azzopardi
2012 - 2016
Rockefeller University

Soyoung Choi
2012 - 2016
Samsung Bioepis

Bu Jung Kim
2014 - 2015
Herbert Wertheim College of Medicine

RIP-Tag; RIP-tva preclinical mouse model
The use of a powerful mouse model, RIP-Tag, has provided significant insights for the molecular mechanism of tumorigenesis in general, far beyond pancreatic neuroendocrine tumors (panNETs). In this model, the rat insulin promoter (RIP) drives the expression of the SV40 T antigen (Tag) in pancreatic β cells. The mice develop tumors through well-defined stages that are similar to human tumorigenesis, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma in four months. However, this valuable preclinical mouse model does not develop metastatic disease.

To investigate molecular networks that drive the progression from primary cancer to metastasis, we have developed a bitransgenic mouse model, RIP-Tag; RIP-tva, in which the receptor for subgroup A avian leukosis virus (RIP-tva) is also expressed in pancreatic β cells. As such, genetic alterations can be introduced in vivo into pancreatic β cells by infection with avian retroviral vectors harboring desired genetic alteration (Figure 1). This approach has the advantage of introducing somatic genetic changes specifically into premalignant lesions of pancreatic β cells in a time-control manner, thus more faithfully mimicing sporadic tumor development. This approach also avoids any potential perturbation of normal tissue formation often observed in conventional transgenic models due to the ectopic expression of the gene of interest during development. In parallel, using cell lines derived from pancreatic neuroendocrine cell tumors in RIP-Tag; RIP-tva mice, further biochemical and cellular analysis can be easily performed in vitro.




The RCAS-tva system
https://home.ncifcrf.gov/hivdrp/RCAS/overview.html




Doxycycline-inducible PyMT mouse model
The cellular origins of the various forms of pancreatic cancer have not been resolved. It is not known whether different pancreatic tumor types arise from transformation or transdifferentiation of different target cells or whether they arise from a common precursor, with tumor types determined by the specific genetic alterations. The pancreas is composed of ductal, acinar, and endocrine cells, which are morphologically and functionally distinct. Resembling the physiologic and cellular diversity of the pancreas is a spectrum of pancreatic malignancies that possess histological and molecular features that recapitulate to some degree the properties of their normal cellular counterparts. In addition, pancreatic tumors with mixed differentiation have been found.

Previous studies suggested that experimental pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells (Yoshida and Hanahan, Am J Pathol, 1994; Lewis et al., Genes Dev, 2003). To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we have generated a transgenic mouse line that inducibly expresses the PyMT oncogene and the linked Luciferase reporter (tet-o-PyMT-IRES-Luciferase) in different cell types. Luciferase bioluminescence emission facilitates monitoring transgene expression in living mice. We found that the ability of PyMT to induce tumorigenesis is dependent upon cell lineages. Conditional activation of PyMT in pancreatic β cells of transgenic mice led to irreversible expansion of the β cell population regardless of the developmental stage at which it was expressed (Figure 2). However, activation of PyMT starting from pancreatic precursor cells induced either lethal acinar cell carcinomas or β-cell hyperplasia. Although continued expression of PyMT was required for maintenance of acinar cell carcinomas, it was not required to maintain the survival of the expanded β cell population, in contrast with all other studies on acquired dependence of hyperplastic/tumor cells on an activated oncogene for their survival.

While losses of functional p53 and p16Ink4a/p19Arf have been identified in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumors (PanNETs), their roles in promoting tumorigenesis of the two pancreatic tumors types has not been previously investigated. We demonstrate that p53 loss in pancreatic progenitor cells results in aggressive PACC, whereas p16Ink4a/p19Arf loss results in PanNETs in the context of PyMT induction. In a model of β-cell hyperplasia, p53 and p16Ink4a/p19Arf play cooperative roles in constraining the progression of PanNETs.

Postdoctoral Fellows
We welcome highly motivated candidates with a recent Ph.D. degree in the field of molecular biology, cancer biology, developmental biology, genomics, or genetics. Ph.D. candidates expected graduation are also encouraged to apply. Applicant must be fluent in English, collegial and able to work independently, with at least one recent first author publication in a high-impact journal. High levels of critical thinking and strong troubleshooting ability are expected.

To apply for a postdoctoral fellowship in the laboratory, please send the following information to Dr. Nancy Du:
  • A detailed curriculum vitae
  • Names and contact information of 3 references
  • Why you are interested in our lab and your post-doctoral training goals




Graduate Students
Our laboratory does not admit graduate students directly. Please apply Weill Cornell Graduate School programs in Biochemistry & Structural Biology, Cell & Developmental Biology, and Molecular Biology (http://gradschool.weill.cornell.edu/) or Tri-Institutional MD-PhD Program (http://www.med.cornell.edu/mdphd). We welcome graduate students interested in rotating in the lab and conducting PhD thesis research.


Undergraduate Students
We accept undergraduate students from Macaulay Honors at Hunter College. Undergraduate students who make significant contributions to research projects can become co-authors of research papers. If you are interest in joining our lab, please contact Dr. Nancy Du by email and include your resume, a transcript, your hours for lab research, and names and contact information of at least 2 references. Priority will be given to students with genuine interest, a strong commitment in research, and excellent grade in relevant science courses.
Shipping/Overnight Address
Dr. Nancy Du
413 E. 69 th Street, C440B
New York, NY 10021
USPS Mailing Address
Dr. Nancy Du
Department of Pathology and Laboratory Medicine
Weill Cornell Medical College
1300 York Avenue, Box 69
New York, NY 10065
Email Address
Lab Phone
+1.212.746.4524
Cancer Search, Molecular Mechanisms, Cancer Metastasis, Mouse Model, Pancreatic Cancer, TVA, Tag, PyMT, RHAMM, Bcl-xL
© 2016 Nancy Du Lab. All rights reserved.