Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Xiao Fu; Yue Zhao; Jose I Lopez; Andrew Rowan; Lewis Au; Annika Fendler; Steve Hazell; Hang Xu; Stuart Horswell; Scott T C Shepherd; Charlotte E Spencer; Lavinia Spain; Fiona Byrne; Gordon Stamp; Tim O'Brien; David Nicol; Marcellus Augustine; Ashish Chandra; Sarah Rudman; Antonia Toncheva; Andrew J S Furness; Lisa Pickering; Santosh Kumar; Dow-Mu Koh; Christina Messiou; Derfel Ap Dafydd; Matthew R Orton; Simon J Doran; James Larkin; Charles Swanton; Erik Sahai; Kevin Litchfield; Samra Turajlic; TRACERx Renal Consortium; Paul A Bates

doi:10.1038/s41559-021-01586-x

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

Nat Ecol Evol. 2022 Jan;6(1):88-102. doi: 10.1038/s41559-021-01586-x. Epub 2021 Dec 23.

Authors

Xiao Fu^#^{1

2}, Yue Zhao^#^{3

4

5

6}, Jose I Lopez⁷, Andrew Rowan³, Lewis Au^{8

9}, Annika Fendler⁸, Steve Hazell¹⁰, Hang Xu^{3

11}, Stuart Horswell¹², Scott T C Shepherd^{8

9}, Charlotte E Spencer^{8

9}, Lavinia Spain^{8

9}, Fiona Byrne⁸, Gordon Stamp¹³, Tim O'Brien¹⁴, David Nicol¹⁵, Marcellus Augustine³, Ashish Chandra¹⁶, Sarah Rudman¹⁷, Antonia Toncheva¹⁸, Andrew J S Furness^{8

9}, Lisa Pickering⁹, Santosh Kumar¹⁹, Dow-Mu Koh^{19

20}, Christina Messiou^{19

20}, Derfel Ap Dafydd²⁰, Matthew R Orton²¹, Simon J Doran¹⁹, James Larkin⁹, Charles Swanton^{3

4

22}, Erik Sahai²³, Kevin Litchfield^{24

25

26}, Samra Turajlic^{27

28}; TRACERx Renal Consortium; Paul A Bates²⁹

Collaborators

TRACERx Renal Consortium:
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 Quezada, Mary Varia, Hema Verma

Affiliations

¹ Biomolecular Modelling Laboratory, The Francis Crick Institute, London, UK.
² Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK.
³ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
⁵ Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁷ Department of Pathology, Cruces University Hospital, Biocruces-Bizkaia Institute, Barakaldo, Spain.
⁸ Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK.
⁹ Renal and Skin Units, The Royal Marsden Hospital, London, UK.
¹⁰ Department of Pathology, the Royal Marsden NHS Foundation Trust, London, UK.
¹¹ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
¹³ Experimental Histopathology Laboratory, The Francis Crick Institute, London, UK.
¹⁴ Urology Centre, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
¹⁵ Department of Urology, the Royal Marsden NHS Foundation Trust, London, UK.
¹⁶ Department of Pathology, Guy's and St. Thomas NHS Foundation Trust, London, UK.
¹⁷ Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
¹⁸ Biobank, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
¹⁹ Division of Radiotherapy and Imaging, Institute of Cancer Research, Sutton, UK.
²⁰ Department of Radiology, Royal Marsden Hospital, London, UK.
²¹ Artificial Intelligence Imaging Hub, Royal Marsden NHS Foundation Trust, Sutton, UK.
²² Department of Medical Oncology, University College London Hospitals, London, UK.
²³ Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK. [email protected].
²⁴ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. [email protected].
²⁵ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [email protected].
²⁶ Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UK. [email protected].
²⁷ Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK. [email protected].
²⁸ Renal and Skin Units, The Royal Marsden Hospital, London, UK. [email protected].
²⁹ Biomolecular Modelling Laboratory, The Francis Crick Institute, London, UK. [email protected].

^# Contributed equally.

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.

Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

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