“Unlinking Regeneration and Tumorigenesis: Implications for drug-discovery in Inflammatory Bowel Disease”

Online via Microsoft Teams

Host: Dr Henry McSorley  

Abstract 

Uncontrolled regeneration leads to neoplastic transformation. Barrier epithelia, such as the intestine, undergo continuous homeostatic and damage-induced tissue renewal and thus need to be tightly regulated to prevent neoplastic transformation, suggesting pathways that disengage tumour growth from regenerative processes must exist. By mining RNAseq datasets from two intestinal damage models and using pharmacological, transcriptomics, and genetic tools we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell and spatial transcriptomics, intestinal organoids, and gain and loss of function experiments, we demonstrated that LXR activation in intestinal epithelial cells induces amphiregulin (Areg) that boosts regenerative responses. Notably, when challenged for tumorigenesis LXR activation triggered adaptive immunity dependent anti-tumour responses. Thus, our work reveals a novel mode of epithelial adaptation to damage where LXR functions as a rheostat that promotes tissue repair while limiting tumorigenesis. 

Our findings on unlinking regeneration and tumorigenesis pave the way for innovative pro-regenerative therapies. This is particularly relevant in conditions such as inflammatory bowel disease (IBD), where existing anti-inflammatory treatments often prove inadequate. Building on these foundations, my overarching goal as an independent group leader is to develop an interdisciplinary research program focused on a novel framework for tissue regeneration while reducing tumour risks. In the short term, I plan to integrate epithelial memory and cell-fate changes into a clinical drug discovery pipeline targeting improved tissue regeneration in IBD. In the long term, these efforts may also provide insights into tissue dysfunction in conditions like age-related decline in regeneration and increased tumorigenesis.