Selection of metastasis competent subclones in the tumour interior
Open accessPublished version of a preprint
Abstract
The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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Recent studies suggest metastatic tumor subclones preferentially originate from the tumor interior partly because necrosis-associated vascular permeability changes promote dissemination.
“Indeed, recent studies suggest that metastatic tumor subclones preferentially originate from the tumor interior due in part to changes in vascular permeability associated with necrosis that promotes tumor cell dissemination [28, 29].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [29]
The Discussion (page unavailable) states that metastatic clear cell renal cell carcinoma subclones preferentially originate in the tumour interior and proposes a model linking central necrosis to their evolution. It does not attribute dissemination to necrosis-associated changes in vascular permeability; its proposed mechanism involves increased copy-number alterations and adaptation to harsh conditions. The finding is also specific to the cancer type studied, rather than metastatic tumours generally. (LLM, conf=0.88)
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Cites
Comprehensive molecular characterization of clear cell renal cell carcinoma
The Cancer Genome Atlas Research Network (2013) · Nature · doi:10.1038/nature12222 · Cited by 3,485 · see citing works
The evolutionary history of lethal metastatic prostate cancer
ICGC Prostate UK Group, Gundem, G., Loo, P. V., Kremeyer, B., Alexandrov, L. B., Tubío, J. M. C., Papaemmanuil, E., Brewer, D. S., Kallio, H. M. L., Högnäs, G., et al. (2015) · Nature · doi:10.1038/nature14347 · Cited by 1,358 · see citing works
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
Integrated molecular analysis of clear-cell renal cell carcinoma
Sato, Y., Yoshizato, T., Shiraishi, Y., Maekawa, S., Okuno, Y., Kamura, T., Shimamura, T., Sato‐Otsubo, A., Nagae, G., Suzuki, H., et al. (2013) · Nature Genetics · doi:10.1038/ng.2699 · Cited by 1,223 · see citing works
Gerlinger, M., Horswell, S. D., Larkin, J., Rowan, A., Salm, M., Varela, I., Fisher, R. A., McGranahan, N., Matthews, N., Santos, C. R., et al. (2014) · Nature Genetics · doi:10.1038/ng.2891 · Cited by 1,211 · see citing works
Self-citationSystematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., et al. (2010) · Nature · doi:10.1038/nature08672 · Cited by 1,173 · see citing works
Pan-cancer whole-genome analyses of metastatic solid tumours
Priestley, P., Baber, J., Lolkema, M. P., Steeghs, N., de Bruijn, E., Shale, C., Duyvesteyn, K., Haidari, S., van Hoeck, A., Onstenk, W., et al. (2019) · Nature · doi:10.1038/s41586-019-1689-y · Cited by 1,106 · see citing works
The evolutionary history of 2,658 cancers
Gerstung, M., Jolly, C., Leshchiner, I., Dentro, S. C., Gonzalez, S., Rosebrock, D., Mitchell, T. J., Rubanova, Y., Anur, P., Yu, K., et al. (2020) · Nature · doi:10.1038/s41586-019-1907-7 · Cited by 1,057 · see citing works
Self-citationTracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal
Turajlic, S., Xu, H., Litchfield, K., Rowan, A., Chambers, T., Lopez, J. I., Nicol, D. L., O’Brien, T., Larkin, J., Horswell, S. D., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.057 · Cited by 831 · see citing works
Self-citationMolecular landmarks of tumor hypoxia across cancer types
Bhandari, V., Hoey, C., Liu, L. Y., Lalonde, E., Ray, J., Livingstone, J., Lesurf, R., Shiah, Y.-J., Vujcic, T., Huang, X., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0318-2 · Cited by 678 · see citing works
Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal
Turajlic, S., Xu, H., Litchfield, K., Rowan, A., Horswell, S. D., Chambers, T., O’Brien, T., Lopez, J. I., Watkins, T. B. K., Nicol, D. L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.043 · Cited by 663 · see citing works
Self-citationIdentification of neutral tumor evolution across cancer types
Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A., & Sottoriva, A. (2016) · Nature Genetics · doi:10.1038/ng.3489 · Cited by 628 · see citing works
Beroukhim, R., Brunet, J.-P., Napoli, A. D., Mertz, K. D., Seeley, A., Pires, M. M., Linhart, D., Worrell, R., Moch, H., Rubin, M. A., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0146 · Cited by 413 · see citing works
Kumar, V., Abbas, A. K., & Aster, J. C. (2021) · doi:10.33029/9704-6467-0-krb-2022-1-1036 · Cited by 371 · see citing works
A New Role for Hypoxia in Tumor Progression
Coquelle, A., Toledo, F., Stern, S., Bieth, A., & Debatisse, M. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80137-9 · Cited by 214 · see citing works
Variation in genomic landscape of clear cell renal cell carcinoma across Europe
Scélo, G., Riazalhosseini, Y., Greger, L., Létourneau, L., Gonzàlez-Porta, M., Wozniak, M. B., Bourgey, M., Harnden, P., Egevad, L., Jackson, S., et al. (2014) · Nature Communications · doi:10.1038/ncomms6135 · Cited by 190 · see citing works
Bredholt, G., Mannelqvist, M., Stefansson, I. M., Birkeland, E., Bø, T. H., Oyan, A. M., Trovik, J., Kalland, K., Jonassen, I., Salvesen, H. B., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5344 · Cited by 163 · see citing works
Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation
Zeng, H., Jorapur, A., Shain, A. H., Lang, U. E., Torres, R., Zhang, Y., McNeal, A. S., Botton, T., Lin, J., Donne, M. L., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.014 · Cited by 138 · see citing works
Young, S. D., & Hill, R. P. (1990) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/82.5.371 · Cited by 125 · see citing works
The infinite sites model of genome evolution
Ma, J., Ratan, A., Raney, B. J., Suh, B. B., Miller, W., & Haussler, D. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805217105 · Cited by 98 · see citing works
Rao, G., Pierobon, M., Kim, I., Hsu, W., Deng, J., Moon, Y., Petricoin, E. F., Zhang, Y., Wang, Y., & Giaccone, G. (2017) · Scientific Reports · doi:10.1038/s41598-017-06128-9 · Cited by 98 · see citing works
Hypoxia drives transient site-specific copy gain and drug-resistant gene expressionPreprint
Black, J. C., Atabakhsh, E., Kim, J., Biette, K. M., Rechem, C. V., Ladd, B., Burrowes, P. D., Donado, C. A., Mattoo, H., Kleinstiver, B. P., et al. (2015) · Genes & Development · doi:10.1101/gad.259796.115 · Cited by 83 · see citing works
Hoefflin, R., Lahrmann, B., Warsow, G., Hübschmann, D., Spath, C., Walter, B., Chen, X., Hofer, L., Macher‐Goeppinger, S., Tolstov, Y. L., et al. (2016) · Nature Communications · doi:10.1038/ncomms11845 · Cited by 77 · see citing works
Zhang, L., Zha, Z., Qu, W., et al. (2018) · BMC Cancer · doi:10.1186/s12885-018-4773-z · Cited by 76 · see citing works
Endesfelder, D., Burrell, R. A., Kanu, N., McGranahan, N., Howell, M., Parker, P. J., Downward, J., Swanton, C., & Kschischo, M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2664 · Cited by 74 · see citing works
Self-citationP14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3
Zerrouqi, A., Pyrzynska, B., Febbraio, M., Brat, D. J., & Van Meir, E. G. (2012) · Journal of Clinical Investigation · doi:10.1172/jci38596 · Cited by 70 · see citing works
Tumor necrosis can facilitate the appearance of metastases
Bonfil, R. D., Bustuoabad, O. D., Ruggiero, R. A., et al. (1988) · Clinical & Experimental Metastasis · doi:10.1007/bf01784843 · Cited by 60 · see citing works
CDKN2B Regulates TGF β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels
Nanda, V., Downing, K. P., Ye, J., Xiao, S., Kojima, Y., Spin, J. M., DiRenzo, D. M., Nead, K. T., Connolly, A. J., Dandona, S., et al. (2015) · Circulation Research · doi:10.1161/circresaha.115.307906 · Cited by 60 · see citing works
Consecutive seeding and transfer of genetic diversity in metastasis
Heyde, A., Reiter, J. G., Naxerova, K., & Nowak, M. A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819408116 · Cited by 50 · see citing works
Multi-regional Sequencing Elucidates the Evolution of Clear Cell Renal Cell Carcinoma
Ricketts, C. J., & Linehan, W. M. (2018) · Cell · doi:10.1016/j.cell.2018.03.077 · Cited by 46 · see citing works
Li, W., Hou, J., Niu, J., et al. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0295-1 · Cited by 46 · see citing works
p16 Modulates VEGF Expression via Its Interaction With HIF-1α in Breast Cancer Cells
Zhang, J., Lu, A., Li, L., Yue, J., & Lu, Y. W. (2010) · Cancer Investigation · doi:10.3109/07357900903286941 · Cited by 37 · see citing works
Macklin, P. S., Yamamoto, A., Browning, L., Hofer, M., Adam, J., & Pugh, C. W. (2020) · The Journal of Pathology · doi:10.1002/path.5402 · Cited by 33 · see citing works
Cancer as a Social Dysfunction—Why Cancer Research Needs New Thinking
Axelrod, R., & Pienta, K. J. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-18-0013 · Cited by 17 · see citing works
El‐Mokadem, I., Fitzpatrick, J. M., Rai, B., Cunningham, J., Pratt, N., Fleming, S., & Nabi, G. (2014) · BioMed Research International · doi:10.1155/2014/521380 · Cited by 11 · see citing works
Tumor Cohesion and Glioblastoma Cell Dispersal
Foty, R. A. (2013) · Future Oncology · doi:10.2217/fon.13.66 · Cited by 8 · see citing works
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Zhao, T., Chiang, Z. D., Morriss, J. W., LaFave, L. M., Murray, E. M., Del Priore, I., Meli, K., Lareau, C. A., Nadaf, N. M., Li, J., et al. (2022) · Nature · doi:10.1038/s41586-021-04217-4 · Cited by 268 · see citing works
Yamamoto, A., Huang, Y., Krajina, B. A., McBirney, M., Doak, A. E., Qu, S., Wang, C. L., Haffner, M. C., & Cheung, K. J. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214888120 · Cited by 69 · see citing works
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- Authors
- Zhao, Y., Fu, X., Lopez, J. I., Rowan, A., Au, L., Fendler, A., Hazell, S., Xu, H., Horswell, S., Shepherd, S. T. C., Spain, L., Byrne, F., Stamp, G., O’Brien, T., Nicol, D., Augustine, M., Chandra, A., Rudman, S., Toncheva, A., Pickering, L., Sahai, E., Larkin, J., Bates, P. A., Swanton, C., Turajlic, S., TRACERx Renal Consortium, Challacombe, B., Chowdhury, S., Drake, W., Fernando, A., Fotiadis, N., Furness, A., Hatipoglu, E., Harrison-Phipps, K., Hill, P., Horsfield, C., Marafioti, T., Olsburgh, J., Polson, A., Quezada, S., Varia, M., Verma, H., & Litchfield, K.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- The Francis Crick Institute (GB)
- Hospital de Cruces (ES)
- Royal Marsden NHS Foundation Trust (GB)
- Stanford Medicine (US)
- Guy's Hospital (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- St Thomas' Hospital (GB)
- University College Hospital (GB)
- St Bartholomew's Hospital (GB)
- University College London (GB)
- Hammersmith Hospital (GB)
- Cancer Research UK (GB)
- Corresponding author
- Litchfield, Kevin
- ORCID
- Zhao, Yue
- Fu, Xiao
- Lopez, Jose I.
- Rowan, Andrew
- Au, Lewis
- Fendler, Annika
- Hazell, Steve
- Xu, Hang
- Horswell, Stuart
- Shepherd, Scott T. C.
- Spain, Lavinia
- Byrne, Fiona
- Stamp, Gordon
- O’Brien, Tim
- Nicol, David
- Augustine, Marcellus
- Chandra, Ashish
- Rudman, Sarah
- Pickering, Lisa
- Sahai, Erik
- Larkin, James
- Bates, Paul A.
- Swanton, Charles
- Turajlic, Samra
- Challacombe, Ben
- Fotiadis, Nicos
- Furness, Andrew
- Hatipoglu, Emine
- Horsfield, Catherine
- Marafioti, Teresa
- Olsburgh, Jonathon
- Polson, Alexander
- Quezada, Sergio
- Litchfield, Kevin
- Venue
- Nature Ecology & Evolution
- Published
- 2021-05-17
- Volume
- 5
- Issue
- 7
- Pages
- 1033-1045
- ISSN
- 2397-334X (ISSN-L)
- PMC
- PMC7611703
- OpenAlex
- W3163583760
- Cited by
- 95
- References
- 36
- Citations by year
- 2026: 6 · 2025: 30 · 2024: 12 · 2023: 17 · 2022: 20 · 2021: 10
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Ecology & Evolution (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- Wellcome Trust (EU-FP7-, FC001988, FC001169, FC010110, 16584, FC10988, FC001003, FC001144)
- Francis Crick Institute (10988, CC2044, 10009, 10743, 10316, 10169, 10144, FC001003, 10002, 10681, FC001144)
- Cancer Research UK (259303, A18176, 10748, FC001988, FC001003, 29911, FC010110, FC001144, FC10988, C50947/A18176, 16584, 18176, FC001169, C69256/A30194)
- National Institute for Health and Care Research (ACF-2016-22-002, C50947/A18176)
- University College London
- Rosetrees Trust (A2437)
- Medical Research Council (MR/P014712/1, MR/V033077/1, FC001003, FC001144, EU FP7)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- tumor subclones, clear cell renal cell carcinoma, metastasis, somatic copy number alterations, tumor hypoxia, tumor necrosis, driver mutations, tumor heterogeneity
- MeSH terms
- Humans, Mutation, Neoplasms, Evolution, Molecular, Genomics, DNA Copy Number Variations
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