Title: Cellular and Molecular Signature of Oral Squamous Cell Carcinoma
Fatima Qadir was a PhD student under the supervision of Dr Muy-Teck Teh and Dr Ahmad Waseem at Queen Mary, University of London. Her project was funded by Saving Faces, which was a biomarker study that focused on the role of exosomes in oral cancer diagnosis and development.
Update: Fatima Qadir successfully submitted her final thesis and passed her PhD viva with minor corrections in May 2018.
Follow the project log here: https://www.researchgate.net/project/Pattern-recognition-in-human-gene-expression-network
Final PhD report by Fatima
Mouth cancer is the sixth most common cancer worldwide. It is a result of numerous factors such as genetic predisposition, smoking, excessive alcohol consumption and viruses such as the human papilloma virus. Due to late diagnosis it has a high fatality rate.
Currently no screening is available for high risk patients for better monitoring. Diagnosing mouth cancer relies on visually studying sections of tumour tissue under a microscope for abnormal changes. This is an invasive method and requires the patient to give a tissue sample causing much discomfort. Although the technique has been used for decades it fails to identify the molecular changes which appears much before the visual signs. It also falls short in predicting the aggressive nature of the disease and its pace of spread. Identifying preceding molecular changes in cells can aid in a more specific and early diagnosis of the disease.
There is a need to monitor high risk patients through non-invasive methods such as a liquid biopsy, causing less patient discomfort. This study focuses on developing liquid biopsy for early oral cancer diagnosis. We explored the potential use of exosomes, which are small nano size vesicles secreted by normal and cancer cells. They can be isolated from body fluids such as blood and saliva. The basic function of exosomes is cell-cell communication, which able cancer cells to pass their content to neighbouring normal cells. This communication between cells aids in developing disease. In cancer biology exosomes offer the advantage of non-invasive disease detection. In addition they can also be used to monitor disease progression and treatment success.
A protocol was formulated for successful exosome isolation from body fluids including blood and saliva. We report the presence of a potential biomarker that can be used to isolate oral cancer exosomes from a mixed population within body fluids. In future we aim to validate this biomarker on oral cancer patient’s blood and saliva samples. We also aim to develop simpler and less time consuming protocols to determine the levels of oral cancer exosomes in patient samples.
Through characterisation of exosomal contents, their functional significance as modulators of essential cellular functions became evident. To date the role of exosomes in developing oral cancer is largely unknown. In order to understand the molecular changes caused by exosome, normal cells were exposed to cancer exosomes. These cells were further screened for changes in approximately 50,000 genes. We found elevated levels of genes responsible for tumour initiation, development and progression. In addition, low levels of multiple tumour suppressing genes were noted. This suggests that cancer exosomes are capable of transforming normal cells into cancer cells.
In the process of screening 50,000 genes on normal cells exposed to cancer exosomes, we found numerous genes essential for normal cellular function with aberrant expression levels. The role of these genes in the developing oral cancer is currently unknown. In future, we aim to determine their function and involvement in cellular pathways, aiding in establishing disease state. This information will not only aid in early diagnosis but will also be valuable in designing personalised treatment.
In the field of oral cancer, exosome is a new area of research. In the past, the number of exosomes and the duration of exposure time needed by cells to show molecular changes was unknown. In the scope of this study we were able to establish a correlation between exosome dose and exposure time required to cause an effect on cells. This information is not only essential for early diagnosis of oral cancer but also helps us in understanding the role of exosomes in developing disease and its progression.
This study is the stepping stone to establish the use of non-invasive exosome based diagnosis for oral cancer patients. Exosome offer a possible solution to current limitations in the oral cancer diagnostics. Further research is in progress to tap their full potential for clinical translation. A strong collaboration of engineers, biologist, clinicians and policy makers can pave the way for future implementation of exosome technology for patient benefit.
- Clinical correlation of opposing molecular signatures in head and neck squamous cell carcinoma (2019) – BMC Cancer
- Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation (2018) – Molecular Cancer Journal