Eppley Cancer Institute

• NAME/TRAINING:

        Michel M. Ouellette, Ph.D.

Graduate School	Département de Biochimie, Université de Montréal, Montréal, QUEBEC.
Post-doctoral Training	Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, USA

Back to Top

• CONTACT INFORMATION:

Contact Name:	Michel M. Ouellette
Phone Number:	402-559-5556 (office), 402-559-4940 (lab)
e-mail address:	mouellet@unmc.edu

• GRANT SUPPORT (last 3 years):

Source: NIH
Title: SPORE in Gastrointestinal Cancer
Role in Project: Leader of Project 4 - Inhibitors of Telomerase in Pancreatic Cancer
Dates: 10/01/08 - 09/30/13

Source: NIH
Title: Smoking and Pancreatic Cancer
Role in Project: Co-Investigator
Dates: 04/01/08 - 03/31/13

Source: NIH
Title: Early Diagnosis of Pancreatic Cancer
Role in Project: Co-Investigator
Dates: 09/27/04-08/31/09

Source: Eppley Cancer Center Pilot Grant
Title: Role of the alternate DNA-binding activity of telomeric protein POT1
Role in Project: Principal Investigator
Dates: 01/31/07-09/30/08           

Source: Mary Kay Ash Charitable Foundation
Title: Novel Strategies for the Inhibition of Telomerase in Breast Cancer cells
Role in Project: Principal Investigator
Dates: 07/01/05-06/30/08

Source: NIH
Title: Cellular Engineering of Hepatocytes Cell Lines
Role in Project: Co-Investigator
Dates: 03/01/02 - 12/31/06

Source: Susan G. Komen Breast Cancer Foundation
Title: Mutants of human telomerase RNA with cytotoxic activities against breast cancer cells
Role in Project: Principal Investigator
Dates: 05/01/03 - 04/30/05

Back to Top

• PUBLICATIONS (last 3-5 years):

Choi, K.H., Farrell, A.S., and Ouellette, M.M. (2008) Sequence-Specific Recognition of Telomeric DNA Junctions by Native TRF2 Complexes Lacking the Basic Domain. (Submitted for Publication).

Feldmann, G., Habbe, N., Dhara, S., Bisht, S., Alvarez, H., Fendrich, V., Beaty, R., Mullendore, M., Karikari, C., Bardeesy, N, Oullette, M.M., Yu, W., and Maitra, A. (2008) Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut [Epub ahead of print] May 30. 

Moniaux N., Chakraborty S., Yalniz M., Gonzalez J., Shostrom V.K., Standop J., Lele S.M., Ouellette M., Pour P.M., Sasson A.R., Brand R.E., Hollingsworth M.A., Jain M., and Batra S.K. (2008) Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia. Br J Cancer. 98:1540-1547.

Meehan, D.T., Zink, M.A., Mahlen, M., Nelson, M., Sanger, W.G., Mitalipov, S.M., Wolf, D.P., Ouellette, M.M., and Norgren, R.B. Jr. (2008) Gene targeting in adult rhesus macaque fibroblasts. BMC Biotechnology 8: 31.

Campbell, P.M., Lee, K.M., Ouellette, M.M., Kim, H.J., Groehler, A.L., Khazak, V., and Der, C.J. (2008) Ras-Driven Transformation of Human Nestin-Positive Pancreatic Epithelial Cells. Methods in Enzymology 439: 451-465.

Cao, D., Lee, K.M., Itami, A., Pour, P.M., Maitra, A., Hruban, R., and Ouellette, M.M. (2007) Class III β-Tubulin, a Marker of Resistance to Paclitaxel, is Overexpressed in Pancreatic Ductal Adenocarcinoma and Intraepithelial Neoplasia. Histopthaology 51: 539-546.

Ouellette, M.M. and Choi, K.H. (2007) Telomeres and Telomerase in Ageing and Cancer. In: Encyclopedia of Life Sciences (http://www.els.net/). John Wiley & Sons Ltd, Chichester, UK.

Salaria, S.N., Illei, P., Sharma, R., Walter, K.M., Klein, A., Eshleman, J.R., Maitra, A., Schulick, R., Winter, J., Ouellette, M.M., Goggins, M., and Hruban, R. (2007) Palladin is Overexpressed in the Non-neoplastic Stroma of Infiltrating Ductal Adenocarcinomas of the Pancreas, but is only Rarely Overexpressed in Neoplastic Cells. Cancer Biology & Therapy 6: 324-328.

Campbell, P.M., Groehler, A.L., Lee, K.M., Ouellette, M.M., Khazak, V., and Der, C.J. (2007) K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by Raf and phosphatidylinositol 3-kinase signaling. Cancer Research 67: 2098-2106.

Ouellette, M.M., Lee, K.M., and Kortum R. (2006) Immortalization of primary human cells with telomerase. In: Cell Biology: A Laboratory Handbook (3^rd Edition, Editor: Julio E. Celis). Elsevier Science, San Diego, CA.

Lee, K.M., Yasuda, H., Hollingsworth, M.A., and Ouellette, M.M. (2005) Notch2-positive progenitors with the intrinsic ability to give rise to pancreatic ductal cells. Lab. Invest. 85: 1003-1012.

Lawson, T., Ouellette, M., Kolar, C., and Hollingsworth, M. (2005) Culture and immortalization of pancreatic ductal epithelial cells. Methods Mol. Med. 103:113-22.

Kim M., Sgagias M., Deng X., Jung Y.J., Rikiyama T., Lee K., Ouellette M. and Cowan K. (2004) Apoptosis induced by adenovirus-mediated p14ARF expression in U2OS osteosarcoma cells is associated with increased Fas expression. Biochem Biophys Res Commun. 320: 138-144.

Lee K.M., Choi K.H., and Ouellette M.M. (2004) Use of exogenous hTERT to immortalize primary human cells. Cytotechnology 45: 33-38.

Lee K.M., Nguyen C., Ulrich A.B., Pour P.M. and Ouellette M.M. (2003) Immortalization with telomerase of the nestin-positive cells of the human pancreas. Biochem. Biophys. Res. Commun. 301: 1038-1044.

Back to Top

• PREVIOUS GRADUATE STUDENTS/POST-DOCTORAL FELLOWS (present location):

Farrell, Amy, S. (post-doctoral fellow)
Choi, Kyung, H. (post-doctoral fellow)
Lee, Kwang, M. (post-doctoral fellow)
Itami, Atsushi (post-doctoral fellow)
Schneider, Matthias, B. (post-doctoral fellow)
Ulrich, Alexis, B. (post-doctoral fellow)

Back to Top

• CURRENT RESEARCH PROJECTS:

Biochemical Properties of Telomere Bound Protein Complexes
My laboratory is focused on two separate aspects of cancer research: telomere biology and pancreatic cancer. A common theme to both areas is the enzyme telomerase, its role in cancer development and tissue homeostasis. Telomerase is responsible for the maintenance of telomeres, specialized structures that cap the ends of chromosomes. Because most somatic human cells lack telomerase, telomeres shorten each time cells divide and this attrition acts as mitotic clock that limits cellular lifespan. Human telomeres are made of TTAGGG DNA repeats that serve as an anchor for the recruitment of DNA-binding proteins TRF1, TRF2, and POT1. Through protein-protein interactions, these factors recruit a multitude of other proteins to telomeres, with which they form a large DNA/protein capping complex. The integrity of this complex is vital to survival and proliferation, but is compromised by the shortening of the telomeres that normally occurs during the aging process. This obstacle to unlimited lifespan is almost always bypassed during cancer development, most frequently by the aberrant re-expression of telomerase. My laboratory seeks to understand the role played by telomerase in the development of malignancies, and more specifically its synergy with other oncogenic insults. A second area of interest pertains to the structure of human telomeres and how changes in this structure can affect the proliferation and survival of human cells, both normal and cancerous. Current projects are focused on the biochemical properties of TRF2 and POT1; their interactions with DNA and proteins, novel activities, structure-function relationships, and impacts on telomere structure.

 

Telomerase Inhibitors in Pancreatic Cancer Therapy
In a separate project, we are studying the effects of telomerase inhibition in pancreatic cancer cells. Our lead compound, GRN163L, is a N3’-P5’ thio-phosphoramidate oligonucleotide that carries a palmitoyl moiety to facilitate cellular uptake. With high affinity and specificity, GRN163L hybridizes to the RNA template of telomerase, thereby blocking its activity. With IC₅₀ in the nanomolar range, GRN163L inhibits telomerase in a large spectrum of cancer cells lines, including pancreatic cancer cells. Continuous exposure of cancer cells to GRN163L leads to telomere attrition, reduction in cellular lifespan, and the induction of apoptosis. In animal models of breast, lung and liver cancer, GRN163L alone was sufficient to limit the lifespan of tumor cells, reduce tumorigenicity, and block metastasis. In my lab, GRN163L is being evaluated for the treatment of pancreatic cancer. We are especially interested in the effects of the drug on cancer stem cells, and in particular their capacity to self-renew. The survival of these cancer stem cells following conventional therapy has been proposed to be responsible for the high incidence of recurrences observed in pancreatic cancer patients. In mice carrying pancreatic tumors, the effects of GRN163L on tumor growth, metastasis, and recurrences will be investigated. The experiments are designed to provide the necessary knowledge for the design of a clinical trial to test GRN163L in pancreatic cancer patients.

Despite significant advances in understanding the disease, recurrences almost invariably occur. This failure to treat may be due to rare tumor cells with properties of stem cells. Hence, current therapies have been optimized for the killing of bulk tumor cells and may not be targeting the cancer stem cells, the survival of which leading to recurrences. To reconstitute tumors, a critical property of cancer stem cells is their ability to self-renew over successive rounds of cell divisions. In human cancers, this capacity for unlimited growth requires telomerase, the enzyme that maintain telomeres. Alas, little is known of the effects of telomerase inhibition on cancer stem cells, as past studies have focused on bulk tumor cells. Our objective is to investigate the impacts of telomerase inhibitor GRN163L on pancreatic cancer stem cells.

Back to Top

• SPECIALIZED LABORATORY/CLINICAL RESEARCH RESOURCES:

Not Applicable

Back to Top