Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER
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.
Authors
- Cristina Naceur‐Lombardelli (ORCID: https://orcid.org/0000-0002-7097-0307)
- Gary Royle (ORCID: https://orcid.org/0000-0002-8548-7684)
- Simone Zaccaria (ORCID: https://orcid.org/0000-0002-5265-7392)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Mark S. Hill (ORCID: https://orcid.org/0000-0003-0718-8934)
- Sophia Ward (ORCID: https://orcid.org/0000-0002-6777-5279)
- Olivia Lucas (ORCID: https://orcid.org/0000-0001-8169-7767)
- Sonya Hessey (ORCID: https://orcid.org/0000-0001-9856-424X)
- Alexander M. Frankell (ORCID: https://orcid.org/0000-0002-0341-7878)
- Abigail Bunkum (ORCID: https://orcid.org/0000-0002-7753-9421)
- Boyue Ding
- Mariam Jamal‐Hanjani (ORCID: https://orcid.org/0000-0003-1212-1259)
- Rija Zaidi (ORCID: https://orcid.org/0000-0002-2259-4319)
- Andrew Rowan (ORCID: https://orcid.org/0000-0003-1926-9707)
- Nicholas McGranahan (ORCID: https://orcid.org/0000-0001-9537-4045)
- Daniele Marinelli (ORCID: https://orcid.org/0000-0002-6002-363X)
- Nnennaya Kanu (ORCID: https://orcid.org/0000-0001-7232-1952)
- David Allan Moore (ORCID: https://orcid.org/0000-0002-6296-1312)
- Michelle Dietzen (ORCID: https://orcid.org/0000-0002-6853-7563)
- Samuel Aparício (ORCID: https://orcid.org/0000-0002-0487-9599)
- Hao-Ran Zhai (ORCID: https://orcid.org/0000-0002-9418-292X)
- Wing Kin Liu
- Emilia L. Lim (ORCID: https://orcid.org/0009-0009-2954-1795)
- Sukhveer Kaur Purewal-Mann
Institutions
- University of British Columbia (CA)
- The Francis Crick Institute (GB)
- Royal London Hospital (GB)
- Cancer Research UK (GB)
- London Cancer (GB)
- St Charles Hospital (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- Genomics (United Kingdom) (GB)
- University College London (GB)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Nature Genetics
- Published
- 2024-11-29
- DOI
- https://doi.org/10.1038/s41588-024-01989-z
- Citations
- 12
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 3.42
Funders
- Breast Cancer Research Foundation
- Wellcome
- Cancer Research UK
- Rosetrees Trust
- Medical Research Council