Ludwig Cancer Research Oxford - Xin Lu
Richard Owen, David Severson, Michael White, Barbara Braden, Adam Bailey, Elizabeth Bird-Lieberman, Mark Middleton, Benjamin Schuster-Böckler and Xin Lu
We are developing single cell RNA-seq projects focussed on understanding cellular evolution and heterogeneity in normal upper gastrointestinal epithelia, oesophageal cancer, and oesophageal premalignant lesions.
1. Characterisation of the human upper gastrointestinal tract epithelial transcriptome:
We have demonstrated that histologically related tissues exhibit starkly different gene expression patterns between sampling sites in the upper gastrointestinal tract (duodenum, stomach and oesophagus). The cells that exist in the transitional epithelial site in the lower oesophagus display a mixed transcriptional profile that is not well understood. We aim to build models of cellular hierarchy and relate this to known cell subtypes by transcriptomic profiling of epithelial cells isolated from endoscopic biopsies. Through single cell subtype identification we also aim to explore whether mixed differentiated cell types or mixed transcriptional activity in individual cells accounts for the unexpected transcriptional profile seen in whole tissue.
2. Exploration of cellular heterogeneity and evolution in metaplastic/junctional epithelium:
In addition to normal tissues, we are investigating the transcriptional profile and cellular heterogeneity in a specific condition manifested by expansion of junctional tissue phenotype and malignant potential (Barrett’s oesophagus). We are extending this study to dysplastic and malignant oesophageal epithelium to identify the initiating cell niche driving disease progression.
3. Pathway dysregulation in normal-to-cancer progression in the oesophagus:
Previous published work suggests early mutation of key oncogenic signalling pathways in Barrett’s oesophagus, prior to malignant development. Our preliminary data shows these dysregulations may occur earlier than expected; hence providing a tractable approach to recognise malignant progression far in advance of current diagnostic methods. We aim to use this knowledge, along with single cell and matched whole tissue samples, to inform analysis of pathway dysregulation within cell subtype niches and potentially at a cellular level to predict disease course.
Epithelial cell and leukocyte response to immunotherapy in vivo
As part of a phase I/II clinical trial applying immunotherapy to patients with oesophageal cancer, leukocytes and epithelial cells will be isolated from tissue samples obtained in treatment naïve and immunomodulated samples. Using single cell RNA-seq we aim to understand the leukocyte and epithelial responses to immunotherapy, and explore relationships between epithelial cells and leukocytes at a transcriptomic level.