Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study
Xiao Fu, Yue Zhao, José I. López, Andrew Rowan, Lewis Au, Annika Fendler, Steve Hazell, Hang Xu, Stuart Horswell, Scott T.C. Shepherd, Charlotte Spencer, Lavinia Spain, Fiona Byrne, Gordon Stamp, Tim O’Brien, David Nicol, Marcellus Augustine, Ashish Chandra, Sarah Rudman, Antonia Toncheva, Andrew Furness, Lisa Pickering, Santosh Kumar, Dow‐Mu Koh, Christina Messiou, Derfel ap Dafydd, Matthew Orton, Simon Doran, James Larkin, Charles Swanton, Erik Sahai, Kevin Litchfield, Samra Turajlic, Ben Challacombe, Simon Chowdhury, William Drake, Archana Fernando, Nicos Fotiadis, Emine Hatipoglu, Karen Harrison‐Phipps, Peter Hill, Catherine Horsfield, Teresa Marafioti, Jonathon Olsburgh, Alexander Polson, Sergio A. Quezada, Mary Varia, Hema Verma, Paul A. Bates
Abstract
Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.