Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER

Olivia Lucas; Sophia Ward; Rija Zaidi; Abigail Bunkum; Alexander M Frankell; David A Moore; Mark S Hill; Wing Kin Liu; Daniele Marinelli; Emilia L Lim; Sonya Hessey; Cristina Naceur-Lombardelli; Andrew Rowan; Sukhveer Kaur Purewal-Mann; Haoran Zhai; Michelle Dietzen; Boyue Ding; Gary Royle; Samuel Aparicio; TRACERx Consortium; PEACE Consortium; Nicholas McGranahan; Mariam Jamal-Hanjani; Nnennaya Kanu; Charles Swanton; Simone Zaccaria

doi:10.1038/s41588-024-01989-z

Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER

Nat Genet. 2024 Nov 29. doi: 10.1038/s41588-024-01989-z. Online ahead of print.

Authors

Olivia Lucas^#^{1

2

3

4}, Sophia Ward^#^{2

3

5}, Rija Zaidi^{1

2}, Abigail Bunkum^{1

2

6}, Alexander M Frankell^{2

3}, David A Moore^{2

3

7}, Mark S Hill³, Wing Kin Liu^{2

6}, Daniele Marinelli^{6

8

9}, Emilia L Lim^{2

3}, Sonya Hessey^{1

2

4

6}, Cristina Naceur-Lombardelli², Andrew Rowan³, Sukhveer Kaur Purewal-Mann¹⁰, Haoran Zhai^{2

3}, Michelle Dietzen^{2

3

8}, Boyue Ding¹¹, Gary Royle¹¹, Samuel Aparicio^{12

13}; TRACERx Consortium; PEACE Consortium; Nicholas McGranahan^{2

8}, Mariam Jamal-Hanjani^{2

4

6}, Nnennaya Kanu¹⁴, Charles Swanton^{15

16

17}, Simone Zaccaria^{18

19}

Affiliations

¹ Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK.
² Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
³ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
⁴ University College London Hospitals, London, UK.
⁵ Genomics Science Technology Platform, The Francis Crick Institute, London, UK.
⁶ Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
⁷ Department of Cellular Pathology, University College London Hospitals, London, UK.
⁸ Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
⁹ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
¹⁰ Flow Cytometry Science Technology Platform, The Francis Crick Institute, London, UK.
¹¹ Department of Medical Physics and Biomedical Engineering, University College London, London, UK.
¹² Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
¹³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁴ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [email protected].
¹⁵ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [email protected].
¹⁶ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. [email protected].
¹⁷ University College London Hospitals, London, UK. [email protected].
¹⁸ Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK. [email protected].
¹⁹ Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [email protected].

^# Contributed equally.

PMID: 39614124
DOI: 10.1038/s41588-024-01989-z

Abstract

Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones.

Abstract

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