Ontario Cancer Institute (OCI)
Clinical Studies Resource Centre Member
Ontario Cancer Institute (OCI)
Keywords: leukemia, head and neck cancer, acute promyelocytic leukemia (APL), spectral karyotyping, lovastatin, comparative genomic hybridization |
Identifying Biomarkers of Cancer Initiation, Progression and Recurrence
Work in my laboratory focuses on the application of high throughput technologies -- for example, gene expression microarrays, tissue arrays, ChIP-on-chip, microRNA arrays and protein arrays -- to enhance our understanding of cancer biology. Specifically, we are interested in identifying biomarkers of cancer initiation, progression and recurrence in two types of human cancer: Head and Neck Squamous Cell Carcinoma (HNSCC) and Acute Promyelocytic Leukemia (APL).
Head and Neck Squamous Cell Carcinoma
In this arm of my research laboratory, we are specifically interested in the etiology of oral cancers (OSCCs). The molecular genetic changes involved in oral cancer development are poorly understood. Our work focuses on three major questions:
Acute Promyelocytic Leukemia
- What are the gene(s) involved in recurrence of oral cancer? Approximately 50% of OSCCs recur after surgery. Our current approaches involve analyzing OSCC tumour samples, as well as samples taken from the regions immediately surrounding the tumours, at time of surgery (''surgical resection margins''), in order to identify genes deregulated in the tumour and in the surrounding margin(s), which may be predictive of tumour recurrence.
- What are the steps involved in the development of oral cancer? A significant fraction of OSCCs arise from precursor lesions called leukoplakias. In these studies, we are interested in profiling the genetic changes -- specifically, changes in microRNA expression -- in leukoplakias and comparing them to genetic changes found in tumours.
- What are the underlying genetic differences between OSCCs in young patients (< 45 yrs of age) and older patients (> 45 yrs of age)? OSCCs are strongly associated with the risk factors of alcohol consumption and smoking tobacco. However, younger patients who do not exhibit exposure to either of these two risk factors are still diagnosed with OSCC. Our previous work has demonstrated that genetic differences exist between young and older patients. Specifically, we have observed defective DNA mismatch repair and differential gene expression in young patients compared to older patients. This line of study is aimed at further understanding the genetic differences between young and older patients, and at understanding the role of defective DNA repair in OSCCs.
Leukemias are often associated with chromosomal translocations that give rise to fusion proteins which may deregulate cellular signaling or transcription. Our group cloned and characterized two variant fusion proteins involved in APL, NPM-RAR-alpha and NuMA-RAR-alpha, which are both aberrant transcription factors; we are especially interested in understanding the roles of these fusion proteins in the cell. Specifically, we use cell lines, mouse models and human patient samples in order to understand leukemia biology. The questions we are most interested in include:
- What are the common downstream genetic targets of the APL fusion proteins? APL is associated with seven known fusion proteins, all of which involve the RAR-alpha transcription factor. Yet, all fusion proteins give rise to the same disease. We hypothesize that this is because all fusion proteins have a common set of direct transcriptional targets, and are utilizing gene expression arrays and ChIP-on-chip technology to address this issue.
- What are the cell biology effects of the APL fusion proteins? While most studies have focused on the APL fusions as transcription factors, more recent evidence has suggested that these proteins behave distinctly and have effects through protein-protein interactions on other signaling pathways within the leukemic cell. We are applying the same concept as above, and hypothesizing that there may be a common set of interactions and/or deregulated pathways shared by all APL fusion proteins, and are characterizing the protein-protein interactions of the fusions in order to find this out.
- What are the necessary secondary events in leukemia development? Previous studies have indicated that the APL fusions are necessary, but insufficient, for the development of leukemia in mice, suggested that additional genetic ''events'' may cooperate with the fusions in leukemia. We are addressing this question through the above studies, and also through genetic studies of the hCG-NuMA-RAR-alpha mouse model that we previously developed and characterized.
- Dos Reis PP, Bharadwaj RR, Machado J, Macmillan C, Pintilie M, Sukhai MA, Perez-Ordonez B, Gullane P, Irish J, Kamel-Reid S. Claudin 1 overexpression increases invasion and is associated with aggressive histological features in oral squamous cell carcinoma. Cancer. 2008 Dec 1;113(11):3169-80.
- Sukhai MA, Thomas M, Xuan Y, Chan LS, Hamadanizadeh SA, Zhang T, Bharadwaj RR, Schuh AC, Wells RA, Kamel-Reid S. Evidence of functional interaction between NuMA-RARalpha and RXRalpha in an in vivo model of acute promyelocytic leukemia. Oncogene. 2008 Aug 7;27(34):4666-77. Epub 2008 Apr 14.
- Tremblay S, Pintor Dos Reis P, Bradley G, Galloni NN, Perez-Ordonez B, Freeman J, Brown D, Gilbert R, Gullane P, Irish J, Kamel-Reid S. Young patients with oral squamous cell carcinoma: study of the involvement of GSTP1 and deregulation of the Fanconi anemia genes. Arch Otolaryngol Head Neck Surg. 2006;132:958-966.
- Warner, GC, Reis, PP, Jurisica, I, Sultan, M, Arora, S, Macmillan, C, Makitie, AA, Grenman, R, Reid, N, Sukhai, M, Freeman, J, Gullane, P, Irish, J, Kamel-Reid, S. Molecular classification of oral cancer by cDNA microarrays identifies overexpressed genes correlated with nodal metastasis. Int J Cancer 2004;110:857-868.
- Sukhai M, Wu X, Xuan Y, Zhang T, Reis PP, Dube K, Rego E, Bhaumik M, Wells RA, Kamel-Reid S, Pandolfi PP. Myeloid Leukemia with Promyelocytic Features in Transgenic Mice Expressing hCG-NuMA-RAR-alpha. Oncogene 2004;23:665-678.
- Kamel-Reid S, Zhang T, Wells RA. Expression of the NPM-RAR-alpha fusion gene in hematopoietic cells confers sensitivity to troglitazone-induced apoptosis. Oncogene, 2003;22:6424-6435.
- Hummel JL, Zhang T, Wells RA, Kamel-Reis S. The Retinoic acid receptor alpha (RARalpha) chimeric proteins PML-, PLZF-, NPM-, and NuMA-RAR-alpha have distinct intracellular localization patterns. Cell Growth Differ. 2002;13:173-183.
Princess Margaret Hospital
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|Nilva Karla Cervigne|