Relevant Degree Programs
- Treating cancer by targeting tumor microenvironment
- Modulating innate immunity for treatment of melanoma and vitiligo
- Genetic determinants of sweating and anxiety--discovery and clinical translation
- Novel therapeutics for skin inflammation and cancer
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2020)
Cutaneous T-cell lymphoma (CTCL) is a group of lymphoproliferative disorders consisting of two main subtypes: mycosis fungoides (MF) and Sézary syndrome (SS). Due to the lack of robust histological markers, it remains a challenge to establish an accurate diagnosis and offer long term prognostication for CTCL. In addition, the molecular pathogenesis of CTCL is only partially understood. Previously our group discovered that early stage MF skin biopsies contained ectopic expression of TOX gene, which is essential for the early development of CD4⁺ T cells but normally is switched off in mature CD4⁺ T cells in the peripheral tissues. The objectives of my thesis research are to evaluate if TOX can be used to improve CTCL diagnosis and prognostication, and to characterize the functional role of TOX in the pathogenesis of CTCL.Using skin biopsies and clinical databases from Vancouver, Beijing and Boston, I confirmed that TOX expression levels were significantly upregulated in the full spectrum of MF and in SS. In addition, as a diagnostic marker, high TOX expression levels differentiated CTCL from non-CTCL controls with good sensitivity and specificity. Furthermore, as a prognostic marker, high TOX mRNA levels correlated with increased risks of disease progression and disease-specific mortality in MF, and increased risks of disease-specific mortality in SS.I also investigated the functional role of TOX in CTCL pathogenesis using multiple CTCL cell lines and a mouse xenograft model. TOX knockdown in three CTCL cell lines led to markedly increased apoptosis, reduced cell proliferation, and impaired tumorigenic ability. These effects were partially mediated by increased expression of two cell cycle regulators, CDKN1B and CDKN1C. In addition, transcriptome analysis between TOX-suppressed cells and control CTCL cells uncovered additional potential molecules downstream of TOX, such as tumor suppressors FOXO3 and HBP1.Our results provide strong evidence that aberrant activation of TOX can serve as a diagnostic and prognostic biomarker for CTCL. Further, we demonstrated that TOX plays a crucial oncogenic role in CTCL pathogenesis, partially through regulating transcription of CDKN1B, CDKN1C and other downstream genes. Therefore TOX and/or its downstream genes may be promising therapeutic targets for CTCL.
Cancer therapy recently experienced remarkable advances with better understanding of cancer pathogenesis and introduction of new intervention strategies. Biomarkers reflective of the presence of tumor cells, or linked with clinical outcomes, have potential to improve the management of cancers. The purpose of this thesis study is to identify novel biomarkers of human cancers based on tissue microarray (TMA) technology and to determine their value for clinical application in cancer management using melanoma as the model. Melanoma arises from uncontrolled proliferation of melanocytes. Although melanoma accounts for only 4% of all skin cancer, it is responsible for 80% of deaths related to skin malignancies. To discover novel biomarkers of melanoma, we constructed a TMA using biopsies from 707 patients with various stages of melanocytic lesions. Using immunohistochemistry and TMA, multiple biomarker candidates were evaluated, and many were found to have significant prognostic value, including expression loss of Fbw7. To further improve the clinical value of these markers, various combinations of individual markers were evaluated, leading to the identification of KAI1 and p27 that together showed much stronger prognostic value than when used as individual markers. Moreover, since there has been a dearth of reliable prognostic markers to offer prognostic information on specific melanoma stages, we identified the AJCC-stage specific prognostic markers, including BRAF protein expression as a prognostic marker for thin melanomas. In that significant prognostic value was found for Fbw7 protein in melanoma, we performed in vitro experiments on this protein in detail. Our data showed that the alpha isoform of Fbw7, located in the cell nucleus, was the dominant form expressed in melanoma. Knock-down of Fbw7α promoted melanoma cell migration, and the MAPK signaling pathway was required for Fbw7 function in melanoma. These findings indicate loss of Fbw7 to be an independent melanoma prognostic marker, and important for the development of malignant behaviors of melanoma cells. This study has demonstrated that the combination of TMAs of cancers with the corresponding clinical database represents a powerful technological platform for biomarker discovery. TMA/clinical database combination-based investigations should be applicable for the investigation of other types of human cancers as well.
Master's Student Supervision (2010 - 2018)
This study focuses on melanoma, a cancer of pigment-producing cells within the skin(melanocytes) which insidiously spreads (metastasizes) throughout the body. Thisdevastating disease often prevents patients from living beyond five years from diagnosis.Treatment options for melanoma are inept, which has necessitated a demand for research onthe molecular mechanisms of melanoma to aid in the development of novel therapeutictargets and treatments.The gene Sineoculis homeobox homolog 1 (SIX1) encodes for a homeoproteintranscription factor which is an important developmental regulator during embryogenesis. Apreliminary microarray analysis found that SIX1 was upregulated in melanoma. The purposeof this study was to pioneer the assessment of SIX1 in melanoma, including its role in themetastatic functions of melanoma in vitro as well as its clinical relevance. The specific aimsincluded: (1) to assess SIX1 expression in melanoma cell lines and clinical samples; (2) toinvestigate the functional significance and pathogenic role of Six1 in vitro; and (3) toevaluate Six1’s clinical significance in relation to prognosis and clinicopathologicalcharacteristics.Cell lines and clinical samples were tested for SIX1 transcript level using qPCR andprotein level using Western Blotting. Next, two malignant melanoma cell lines weretransfected with shRNA plasmids to generate stable clones with low Six1 expression. Thesealtered cell lines were used to study the functional implications of Six1 expression disparitiesin vitro. Furthermore, immunohistochemistry against Six1 was performed on a tissuemicroarray of 438 melanoma patient biopsies.We discovered that SIX1 was overexpressed in melanoma cell lines and clinicalsamples. Six1 knockdown cells demonstrated diminished cell growth and proliferation,increased apoptosis, and decreased migration and invasion. We also found that a profoundnuclear to cytoplasmic shift of Six1 accompanied melanoma progression and correlated withpoor five-year survival. Higher cytoplasmic Six1 was associated with increased tumorthickness, lower nuclear Six1 with ulceration and histological satellitosis, and both withadvanced AJCC stages and nodular melanoma.To summarize, these results hint that Six1 may play a role in the execution ofmetastatic functions in melanoma. Furthermore, Six1 presents as a tentative candidate for aprognostic marker in patient biopsies.
Background: Melanoma is a devastating cancer with 17% 5-year survival rate when it is metastasized. Clinically, finding new biomarkers will provide more options in patient early diagnosis and treatments. Previously, Lysyl Oxidase-like 3 (LOXL3) was discovered as one of the most upregulated genes in metastatic melanoma compared to normal nevi and normal skin. LOXL3 is an extracellular protein that induces the cross-linkage formation in collagen and elastin. LOXL3 has never reported in melanoma and barely been studied in tumours. The previous knowledge about LOXL3 makes it an attractive gene to study in melanoma.Objective: The objectives of this study are to investigate LOXL3 expression profile, bio-functions, clinical significance, and potential downstream regulators in melanoma.Experimental Methods: A panel of cell lines and tissues was utilized to evaluate LOXL3 expression in mRNA and protein levels. Two melanoma cell lines, A375 and WM-115, were transfected with siRNAs to create transiently-decreased LOXL3 expression, to study the functional differences of LOXL3 in vitro. Further, immunohistochemical staining of tissue microarray with 373 biopsies was used to observe the correlation between LOXL3 expression levels and patient survival outcomes. Results: We detected a significantly higher expression of LOXL3 on mRNA and protein levels in melanoma compared to melanocytes and normal skins. LOXL3 deficiency could inhibit proliferation, migration and invasion in vitro. Tissue microarray revealed that higher LOXL3 cytoplasmic staining was associated with thicker tumour, the presence of mitosis, more advanced melanoma, and worse primary melanoma patient survival. LOXL3 knockdown did not induce any differences in FAK/Src phosphorylation levels or E-cadherin expression levels.Discussion: LOXL3 promotes cell proliferation, cell motility and cell invasion in vitro, and LOXL3 cytoplasmic overexpression is associated with enhanced tumour mitosis and thickness in melanoma in vivo. This suggests LOXL3 has an essential impact on melanoma growth and potentially metastasis due to the invasive potential. In addition, no correlations are found in FAK/Src activation and E-cadherin restoration by LOXL3, suggesting LOXL3 may use a different pathway beyond previous knowledge.Conclusion: LOXL3 positively regulates cellular growth and invasion in melanoma cells and tissues, making LOXL3 a promising prognostic marker and a therapeutic target.
Background: Vitiligo is a complex autoimmune skin condition characterized by the death of melanocytes, the principle pigment producing cells in the skin. Transcriptome analysis of vitiligo skin revealed significantly reduced levels of proteolipid 1 (PLP1) gene, which is known to be expressed by Schwann cells, as well as significantly up-regulation of genes that are associated with natural killer (NK) cell activity.Hypothesis and Objectives: Schwann cells may be adversely affected in vitiligo and NK cells may potentially play a role in the overall disease pathogenesis. Therefore, the purpose of this study is to characterize the down-regulation of PLP1 and assess the presence of NK cell infiltration in vitiligo skin biopsies.Materials and Methods: PLP1 expression analyses were performed on major types of skin cells as well as vitiligo and normal skin samples. Quantification of Schwann cells was performed on paired vitiligo samples using immunohistochemistry. Schwann cell conditioned medium was also tested for its ability to support the growth and survival of human melanocytes. To assess NK cell activity, explant skin cultures and immunofluorescence analyses were performed to localize activated NK cells in skin biopsies.Results: Schwann cells were the primary source of PLP1 in human skin, although it is also expressed by melanocytes. Schwann cells were found to be decreased in vitiligo lesional skin as compared to peri-lesional and normal skin. In addition, conditional medium prepared from cultured Schwann cells significantly increased the survival of human melanocytes. Furthermore, explant skin cultures and immunofluorescence studies revealed marked increase of NK cells with heightened activity in vitiligo lesional as well as peri-lesional vitiligo skin.Conclusion: Results from our study suggest that the loss of melanocytes and reduction in Schwann cells may account for the down-regulation of PLP1 in vitiligo lesional skin. In addition, Schwann cells may play a role in the growth and survival of melanocytes and their decrease may have facilitated the development of vitiligo. Furthermore, this study lends support to the direct involvement of NK cells in the pathogenesis of vitiligo and suggests that they should be explored as cellular targets for development of better therapies in the future.