Current Projects
Understanding the heterogeneous phenotype of cells isolated from ascites of ovarian cancer patients before and after chemotherapy
The presence of ascites has been associated with a poor prognosis. However, the origin and phenotype of the cellular content of ascites and its association with chemoresistance and recurrence is poorly understood. Recently, we have developed a novel method of isolating tumour cells from the ascites of patients with advanced-stage cancer. Work is in progress to identify the molecular differences between single cells and cellular aggregates of ascites collected from patients before and after chemotherapy.
Isolation and characterization of ovarian cancer stem cells
The cellular mechanisms underlying the aggressiveness of ovarian cancer are poorly understood. Evaluation of the similarities between normal and cancer stem cells indicate that the former could be a target of transforming mutations that can give rise to a population of progenitors and differentiated cells that make up the tumour mass. Based on these observations, we hypothesize that the initiation and progression of ovarian cancer may result due to the transformation and dysfunction of stem cells in ovaries. The present study will focus on the establishment, isolation, cloning, propagation and differentiation of stem cells isolated from normal ovaries, tumours from different histological grades of ovarian cancer and multicellular spheroids isolated from ovarian cancer patients.
Ovarian cancer stem cells and their role in chemotherapy resistance
Recent research in our laboratory has identified ovarian cancer cells with characteristics of cancer stem cells after treatment with chemotherapy in vitro. We hypothesize that: (i) the combination drugs (taxol and platinum), commonly used as first line chemotherapy for ovarian cancer patients activate the cellular pathways resulting in the acquisition/enrichment of cells with cancer stem cell-like phenotype ; and (ii) targeting the pathways using specific inhibitors will abrogate this phenotype and sensitize cells to chemotherapy. Hence, our overall aim is to characterize the cancer stem cell like signature in samples collected from ovarian cancer patients before and after chemotherapy treatments. We are using novel small molecule inhibitors in combination with chemotherapy to see if we can abrogate the cancer stem cell like characteristics in samples collected from patients. We are interested in extending these findings to other selective compounds known to have cytotoxic effects on cancer stem cells in other tumours.
MicroRNA profile associated with ovarian cancer chemoresistance
MicroRNAs (miRNA) are small non-coding RNA which can programmatically modulate gene expression through translational repression and mRNA destabilization and/or cleavage. We propose that evaluating miRNA is a robust way of refining the changes in gene expression seen at the mRNA level after chemotherapy treatment. We are seeking to identify and characterize chemoresistance and cancer stem cell like specific microRNAs in tumour cells isolated from ovarian cancer patients. Technology being used is miRNA sequencing. Ongoing work includes identification, validation and functional studies. We expect to identify miRNA and their predicted mRNA targets that are responsible for regulating key chemoresistant targets in primary and metastatic tumours in response to chemotherapy.
Student Projects available
Characterization of cross-talk between tumour and stromal cells in inducing metastasis and resistance to chemotherapy in ovarian cancer
Peritoneal dissemination of ovarian cancer is dictated by the extent of invasiveness in the tumour cells of ascites that survive as peritoneal tumour aggregates (PTCs), and is largely dependent on the biological changes induced by the surrounding stroma. We hypothesize that identification of cross talk between tumour PTCs and stroma will successfully identify potential molecules involved in the predisposition of the tumour cells to metastasize locally as well as respond to chemotherapy. Hence, the aims of this project is: (i) to determine whether cancer associated fibroblasts (CAFs isolated fresh from ascites) can alter the spheroid forming and invasive ability of ovarian cancer cell lines in vitro; & (ii) to determine if CAFs can alter the response of ovarian cancers to chemotherapy by inducing cancer stem cell like characteristics. To achieve these aims PTCs and stromal cells will be isolated from the ascites of ovarian cancer patients and evaluation of the biological alterations induced by the associated stroma will be assessed. The identification of these changes/molecules may lead to the development of novel prognostic indicators.
contact the Women's Cancer Research Centre to discuss.
Elucidating the role of mesenchymal stem cells in promoting metastasis of ovarian cancer cells
Mesenchymal stem cells (MSC) within tumour stroma are derived from the resident tissue or from the circulation or recruited from tissues not related to the tumour. Few recent reports have shown MSC to promote cancer metastasis by initiating paracrine signaling or through enriching the population of ‘tumour initiating cells’ commonly known as ‘cancer stem cells’. Recent data in our laboratory suggests that MSC forms an important component of ascites of ovarian cancer patients. This warrants the need to study the biological alterations (phenotype) induced by MSC on the growth, invasiveness and response to chemotherapy in ovarian cancer cell lines in vitro. This project will compare the inherent traits of MSC and chemotherapy response of ovarian cancer cells in the presence and absence of MSC. MSC will be isolated from the ascites of ovarian cancer patients. Differences in the biological phenotype of ovarian cancer cells in the presence and absence of MSC will be assessed by biochemical assays. The identification of changes/molecules in the presence and absence of MSC may lead to the development of novel therapeutics targeting the effects of MSC on ovarian cancer cells.
contact the Women's Cancer Research Centre to discuss.
Innovative method to target ovarian cancer stem/progenitor cells
Combination chemotherapy (cisplatin and paclitaxel) imposes on residual tumours cancer stem cell-like phenotype resulting in chemoresistant recurrent tumour mass. Targeting cancer stem cell-like markers will provide an opportunity for overcoming chemoresistance and consequently recurrence. The specific aim of this project is to use cell surface aptamers (chemically synthesized, stable, non-immunogeneic and non-cytoxic short single-stranded DNA or RNA) against two currently identified cancer stem cell markers (EpCAM and CD44) to assess the inhibition/reversal of chemoresistance. This project will use a model ovarian cancer cell line which will be treated in vitro with chemotherapeutic drugs to facilitate the expression of stem cell markers CD44 and EpCAM. These cells will be treated with cell surface aptamers against CD44 and EpCAM in the presence and absence of chemotherapy. The cells will be assessed for chemosensitization, alterations in signalling pathways and assessment of proteins which are involved with chemoresistance. Successful completion of the project may provide a model for the development of novel targeted agents which may suppress cancer/recurrence.
contact the Women's Cancer Research Centre to discuss.