Dr. Isabella T. Tai

Titles and Education

Titles

Senior Scientist, BC Cancer Agency, Genome Sciences Centre
Assistant Professor, Division of Gastroenterology, Department of Medicine, University of British Columbia

Education

B.Sc., Physiology, University of Toronto, Canada
M.Sc., Anatomy, University of Toronto, Canada
Ph.D., Physiology, University of Toronto, Canada
M.D., Medicine, University of Toronto, Canada
FRCP(C), Internal Medicine, University of Toronto, Canada
FRCP(C), Gastroenterology, University of Toronto, Canada

Research Interests

Applications are welcome from prospective trainees. For post-doctoral fellows please view current job postings. For graduate students, please contact Dr. Tai at the above email address.

• Gastrointestinal cancers
• Chemotherapy resistance
• Tumour micro-metastasis
• Tumour progression
• Genomics/ proteomics

My laboratory is especially interested in understanding the mechanisms of chemotherapy resistance, metastasis and tumour progression in gastrointestinal cancers using genomics and proteomics approaches. Four main projects are currently underway in the laboratory:

1. Mechanisms of Chemotherapy Resistance in Gastrointestinal Cancers

A genomics approach was undertaken to determine a signature profile of genes that are differentially expressed in chemotherapy resistance in colorectal cancers. Unique signatures were identified that are specific to 5-fluorouracil, irinotecan, etoposide and cisplatin resistance in colorectal cancers, and as well, a profile that represents "global" resistance to chemotherapy. The overall goal of this project will be to develop a "Genomics Map" of Cancer Therapy Resistance. In order to achieve this objective, our laboratory is systematically delineating the importance of these differentially expressed genes in chemo- and radiation therapy resistance in gastrointestinal cancers.

An example of one such gene currently under investigation is SPARC (Secreted Protein Acidic and Rich in Cysteine). SPARC was identified as a putative resistance-reversal-gene by demonstrating low SPARC expression in therapy refractory human MIP101 colon cancer cells. We have been able to demonstrate not only restoration of tumour cell radio-sensitivity and sensitivity to 5-FU and CPT-11 by re-expression of SPARC in tumour xenografts, but as well, significant mouse tumour xenograft regression following treatment with SPARC in combination with chemotherapy. This modulation of SPARC expression affects colorectal cancer sensitivity to radiation and chemotherapy. SPARC-based gene or protein therapy may ameliorate the emergence of resistant clones and eradicate existing refractory clones.

2. Understanding the contribution of chemotherapy resistant cancer cells and the tumour microenvironment in gastrointestinal tumor metastasis

The combination of poor cancer therapy response and the presence of tumour metastasis are responsible for the high mortality rate in cancer. The goals of this project are to understand:

1. the processes that promote the survival of circulating micro-metastases following their dissemination from the primary tumour site
2. the characteristics of the tumour microenvironment that facilitate the survival and seeding of circulating micro-metastases
3. the mechanism of chemotherapy resistance in these micro-metastatic cells

Genomics and proteomics approaches have been undertaken to identify the changes associated with the survival of circulating micro-metastatic cells and with the survival of established distant metastases. This project will provide a greater understanding of the mechanisms involved in metastasis and therapy resistance, revealing targets that are amenable to therapeutic approaches, which may be clinically effective at multiple levels of tumor progression.

3. Identification of Novel Genes Involved in the Colorectal Cancer Progression

Published studies on Serial Analysis of Gene Expression (SAGE) have identified ~56,000 unique genes from 22 libraries constructed from colorectal cancer tissues and cell lines, and 40 genes that are expressed in all cancer tissues, irrespective of origin (Velculescu et al., Nature Genetics 1999). This platform has the unique ability to identify novel transcripts, and hence, novel genes that have not been represented in any EST data set. We have employed this SAGE-platform to identify unknown transcripts representing novel genes involved in the multi-step progression of colorectal cancer development. Novel genes identified in this manner will be studied systematically for their role in colorectal cancer progression and tumorigenesis.

4. CIHR Team in Genomic, Imaging and Modeling Approaches to Advance Population-Based Colorectal Cancer Screening

Colorectal cancer is the second leading cause of cancer-related death in Canada. Due to the high number of false positive results in current screening tests, they are not widely used by health care professionals and the public, which contributes to a higher mortality rate from the disease. The goal of this program is to develop novel easy-to-administer tests that identify individuals at the earliest, most curable stages of the disease. Dr. Tai’s lab will mainly focus on the genomics aspects of the study, and will identify and validate a set of genetic markers that will be suitable for use in screening applications. These screening tests will help to identify people that are at high, medium or low risk of developing polyps and/or colorectal cancer, with the ultimate goal to stratify high-risk individuals for frequent screening, and low-risk individuals for infrequent screening. To achieve these endpoints, the Tai lab uses state-of-the-art genomic techniques, including Affymetrix 500k GeneChip Mapping arrays and subsequent bioinformatic analysis of the data, semi-quantitative RT-PCR, western blot, immunohistochemistry, ELISA and high-throughput tissue microarrays.

Information on the entire project is available on the projects webpage.

Please visit Isabella Tai's Lab Members Page to view current and past lab members.

Select Publications

Crispo JA, Piché M, Ansell DR, Eibl JK, Tai IT, Kumar A, Ross GM, Tai TC. Protective effects of methyl gallate on H₂O₂-induced apoptosis in PC12 cells. Biochem Biophys Res Commun. 2010. Feb 18. [Epub ahead of print]

Khan MA, Steiner Ts, Sham HP, Bergstrom KS, Huang JT, Assi K, Salh B, Tai IT, Li X, Vallance BA. The Single IgGIL-1-Related Receptor Controls TLR Responses in Differentiated Human Intestinal epithelial cells. J Immunol. 2010. 184(5):2305-13. [Epub 2010 Feb 3.]

Chan JH, Ho S, Tai IT. Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by p53. Carcinogenesis. 2010. [Epub ahead of print Feb 17.]

Tai IT, Tang MJ.  SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resistance Updates 2008 Dec;11(6):231-46.

Tai IT. Developing a clinician-scientist career. Clin Invest Med. 2008;31(5): B1-B2.

Cheetham S, Tang MJ, Mesak F, Kenneche H, Owen D, Tai IT. SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2'deoxycytidine to increase SPARC expression and improve therapy response. Br J Cancer. 2008;98(11):1810-9.

Chan SK, Griffith OL, Tai IT, Jones SJ. Meta-analysis of colorectal cancer gene expression profiling studies identifies consistently reported candidate biomarkers. Cancer Epidemiol Biomarkers Prev. 2008;17(3):543-52.

Griffith M, Tang MJ, Griffith OL, Morin RD, Chan SY, Asano JK, Zeng T, Flibotte S, Ally A, Baross A, Hirst M, Jones SJ, Morin GB, Tai IT, Marra MA. ALEXA: a microarray design platform for alternative expression analysis. Nat Methods. 2008;5(2):118.

Taghizadeh F, MJ Tang and IT Tai. Synergism between vitamin D and secreted protein acidic and rich in cysteine-induced apoptosis and growth inhibition results in increased susceptibility of therapy-resistant colorectal cancer cells to chemotherapy. Mol Cancer Ther. 2007;309-317.

Tang MJ and IT Tai. A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in colorectal cancers. J Biol Chem. 2007.

Tai IT, M Dai, DA Owen and LB Chen. Genome-wide expression analysis of therapy resistant tumors reveals SPARC as a novel target for cancer therapy. J Clin Invest. 2005; 115(6):1492-1502

Tai IT, M Dai and LB Chen. Periostin induction in tumor cell line explants and inhibition of in-vitro cultured cell growth by anti-periostin antibodies. Carcinogenesis. 2005;26(5):908-15.

Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O’Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez-Castro D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WB, Munshi NC, Morgan GJ, Anderson KC. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood. 2003;102:4504-4511.

Isabella Tai's Complete Publications List including selected links to full text articles.