Remodelling the Precancerous Niche: A Determinant of Early Tumour Persistence
Maria P. Alcolea
Associate Professor, Cambridge Stem Cell Institute/ Department of Physiology, Development and Neuroscience, University of Cambridge, UK
The Alcolea laboratory focuses on understanding how epithelial stem and progenitor cells adapt their behaviour in response to tissue perturbations, with particular emphasis on epithelial plasticity during injury repair and the earliest stages of cancer development. Combining genetic lineage tracing, quantitative approaches, and innovative 3D organ culture systems, the lab has revealed the remarkable ability of squamous epithelial cells to reprogramme their fate and identity in response to environmental cues.
In this lecture I will discuss how interactions between mutant epithelial cells and their surrounding microenvironment influence the earliest steps of tumour formation. Using the mouse oesophagus as a model system, we have shown that nascent squamous tumours actively remodel their local environment from inception. Early tumour cells trigger stress-response programmes that instruct the underlying mesenchyme to generate a supportive “pre-cancer niche”, characterised by fibroblast activation, extracellular matrix remodelling, and the formation of a fibronectin-rich stromal scaffold that promotes tumour survival and growth. Functional heterotypic 3D culture assays and in vivo grafting experiments further demonstrate that tumour-associated stroma alone can confer tumour-like properties to otherwise healthy epithelial cells.
We propose a model in which cancer susceptibility is determined not only by genetic alterations within epithelial cells, but also by the dynamic response of neighbouring stromal cells to early oncogenic stress.
Ongoing work is further exploring how genetic alterations impact epithelial fate plasticity and stromal interactions, thereby determining susceptibility to tumour formation and progression. Our vision is to explore new avenues to halt tumour formation in its tracks.
