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 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.

Automated summary

This study utilizes highly multiplexed tissue imaging to quantitatively analyze cell cycle regulators in cancer cells. The results show that proliferative architecture in tumors consists of large domains and smaller niches enriched with specific immune lineages. Some tumor cells exhibit cell cycle coherence, while others show non-canonical marker combinations. Changes in coherence are associated with oncogene activity and therapeutic intervention, and correlate with aggressive tumor behavior.