Many cancers originate from precancerous lesions, each carrying varying risks of malignant progression. Understanding the cell of origin of these lesions and the drivers of malignant progression is crucial for early detection, risk stratification, and early intervention in cancer.
My research primarily focuses on oesophageal adenocarcinoma (OAC) and its precursor, Barrett's oesophagus (BO). OAC is a lethal cancer often diagnosed at an advanced stage, and its incidence is increasing in Western countries. BO is a relatively common condition, affecting approximately 1 in every 200 individuals. The current challenges include the discomfort associated with long-term, invasive surveillance for patients and the significant burden placed on public health sectors, such as the NHS, due to large-scale surveillance efforts.
Using BO and OAC as a disease model, my research endeavours to address a fundamental question: how do early-stage cancers or their precursors emerge from normal tissue, and to what extent can we decipher their risk of progression? My research explores both intrinsic and extrinsic factors that initiate BO and OAC.
Firstly, I have established a series of patient derided organoid models from normal tissues, BO, and OAC, and examine the lineage relationships among these organoids representing different clones from different disease stages, allowing us to map an evolutionary trajectory and giving insights of how clones are selected in cancer initiation and development. It is conceivable that certain cancer-related 'bad seeds' may manifest even before cancer fully develops, shedding light on the optimal timing for early cancer detection.
Secondly, our research seeks to identify the tissue microenvironment surrounding these 'seeds' and compare extrinsic factors in patients known to progress to more advanced disease with those who do not progress. This investigation will help determine whether these factors play a role in disease progression.
Thirdly, we will select a subset of 'seeds' and microenvironmental factors of interest for functional validation, enabling direct experimentation to explore their interactions and competition, ultimately leading to malignancy or a more indolent state.
Through this research, I seek to answer bigger questions regarding the cell origin of cancer and its precancerous lesions, its evolutionary trajectory, and how we can modulate this process to develop new strategies for early detection, treatment, and prognosis.