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

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journal contribution
posted on 2025-01-16, 11:01 authored by 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
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.

Funding

Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC1062, Grant title: STP Flow Cytometry) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS) Crick (Grant ID: CC1064, Grant title: STP Genomics)

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