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:
- the processes that promote the survival of circulating micro-metastases following their dissemination from the primary tumour site
- the characteristics of the tumour microenvironment that facilitate the survival and seeding of circulating micro-metastases
- 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.
Wong J, Hasan M, Rahman M, Yu A, Chan S, Schaeffer D, Kennecke H, Lim H, Owen D, Tai IT. Nucleophosmin 1, upregulated in adenomas and cancers of the colon, inhibits p53- mediated cellular senescence. Int J Cancer. 2013 Mar 28. 4 doi: 10.1002/ijc.28180. [Epub ahead of print]
Short MA, Tai IT, Owen D, Zeng H. Using high frequency Raman spectra for colonic neoplasia detection. Optic EXPRESS. 2013 Feb 25;21(4):5025-34.
Mansoor H, Zeng H, Tai IT, Zhao J, Chiao M. A Handheld Electromagnetically Actuated Fiber Optic Raster Scanner for Reflectance Confocal Imaging of Biological Tissues. IEEE Trans Biomed Eng. 2013 May;60(5):1431-8. doi: 10.1109/TBME.2012.2236326.
Rahman M, Selvarajan K, Hasan MR, Chan AP, Jin C, Kim J, Chan SK, Le ND, Kim YB, Tai IT. Inhibition of COX-2 in Colon Cancer Modulates Tumor Growth and MDR-1 Expression to Enhance Tumor Regression in Therapy-Refractory Cancers In Vivo. Neoplasia. 2012 July 14(7): 624-33.
Griffith M, Mwenifumbo JC, Cheung PY, Paul JE, Pugh TJ, Tang MJ, Chittaranjan S, Morin RD, Asano JK, Ally AA, Miao L, Lee A, Chan SY, Taylor G, Severson T, Hou YC, Griffith OL, Cheng GS, Novik K, Moore R, Luk M, Owen D, Brown CJ, Morin GB, Gill S, Tai IT, Marra MA. Novel mRNA isoforms and mutations of uridine monophosphate synthetase and 5-fluorouracil resistance in colorectal cancer. Pharmacogenomics. 2013 Apr;13(2):148-58. doi: 10.1038/tpj.2011.65.
Rahman M, Chan APK, Tai IT. A peptide of SPARC interferes with the interaction between caspase8 and Bcl2 to resensitize chemoresistant tumors and enhance their regression in vivo. PLoS One. 2011;6(11):e26390.
Hasan MR, Ho SHY, Owen D, Tai IT. Inhibition of VEGF induces cellular senescence in colorectal cancer cells. Int J Cancer. 2011 Nov 1;129(9):2115-2123.
Wong JCT*, Chan SK*, Schaeffer DF, Sagaert X, Lim H, Kennecke H, Owen D, Suh KW, Kim YB, Tai IT. Absence of MMP2 expression correlates with poor clinical outcomes in rectal cancer, and is distinct from MMP1-related outcomes in colon cancer. Clinical Cancer Research. 2011 Jun 15;17(12):4167-76. (*Shared first author).
Isabella Tai's Complete Publications List including selected links to full text articles.