Temporal and spatial topography of cell proliferation in cancer

Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation met...

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Published in	Nature cell biology Vol. 24; no. 3; pp. 316 - 326
Main Authors	Gaglia, Giorgio, Kabraji, Sheheryar, Rammos, Danae, Dai, Yang, Verma, Ana, Wang, Shu, Mills, Caitlin E., Chung, Mirra, Bergholz, Johann S., Coy, Shannon, Lin, Jia-Ren, Jeselsohn, Rinath, Metzger, Otto, Winer, Eric P., Dillon, Deborah A., Zhao, Jean J., Sorger, Peter K., Santagata, Sandro
Format	Journal Article
Language	English
Published	London Nature Publishing Group UK 01.03.2022 Nature Publishing Group
Subjects	13/105 13/106 13/51 14/1 14/63 631/1647/328 631/553/1833 631/553/2706 692/699/67/2321 692/699/67/2329 82/80 96 Biomedical and Life Sciences Cancer Cancer Research Cell Biology Cell Cycle Cell Proliferation Coherence Developmental Biology Humans Life Sciences Markers Multivariate analysis Neoplasms - genetics Spatial distribution Stem Cells Tumors
Online Access	Get full text
ISSN	1465-7392 1476-4679 1476-4679
DOI	10.1038/s41556-022-00860-9

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Summary:	Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages. Some tumour cells express cell cycle regulators in the (canonical) patterns expected of freely growing cells, a phenomenon we refer to as ‘cell cycle coherence’. By contrast, the cell cycles of other tumour cell populations are skewed towards specific phases or exhibit non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity and therapeutic intervention, and is associated with aggressive tumour behaviour. Thus, multivariate measures from high-plex tissue images capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies. Gaglia, Kabraji and colleagues quantify cell cycle markers in single cells to define the spatial distribution of proliferation in tumours. They define metrics that capture clinically significant features of cancer proliferation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authors Contributions Statement These authors contributed equally to this work GG, SK, JJZ, PKS, and SS were responsible for study conceptualization. GG, SK, SW, CEM, JB, SC, JRL, PKS, and SS developed and implemented the methodology. GG, SK, DR, YD, AV, CEM, MC, and SC conducted data acquisition. GG, DR, and YD generated software. GG, SK, DR, YD, SC, DAD, and DR performed data validation. GG, SK, DR, YD, AV, CEM, and SC performed formal analysis. JB, DAD, RJ, OM, EPW provided resources. GG, SK, DR, YD, SC, and DAD performed data curation. GG, SK, SS wrote the original draft and all authors reviewed and edited the manuscript. Data visualization was conducted by GG, SK, YD, and DR. JJZ, PKS, SS provided project supervision and PKS and SS provided project administration. EPW, JJZ, PKS, and SS provided resources and funding.
ISSN:	1465-7392 1476-4679 1476-4679
DOI:	10.1038/s41556-022-00860-9