Temporal and spatial topography of cell proliferation in cancer

Proliferation is a fundamental trait of cancer cells but is poorly characterized in tumors by classical histologic methods. We use multiplexed tissue imaging to quantify the abundance of multiple cell cycle regulating proteins at single-cell level and develop robust multivariate proliferation metrics. Across cancers, the proliferative architecture is organized at two distinct spatial scales: large domains, and local niches enriched for specific immune lineages. A subset of tumor cells express cell cycle regulators in canonical patterns consistent with unrestrained proliferation, a phenomenon we refer to as “cell cycle coherence”. By contrast, the cell cycles of other tumor cell populations are skewed toward a specific phase or characterized by non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity, and with therapeutic intervention, and is associated with aggressive behavior. Multivariate measures capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies. ### Competing Interest Statement PKS is a member of the Scientific Advisory Board of RareCyte Inc. and NanoString Technologies. PKS is co-founder of Glencoe Software, which contributes to and supports the open-source OME/OMERO image informatics software used in this paper. SS is a consultant for RareCyte, Inc.. JJZ is a founder and board director of Crimson Biotech and Geode Therapeutics. JSB is a scientific consultant and has stock options for Geode Therapeutics Inc. DAD is on the Advisory Board for Oncology Analytics and has consulted for Novartis. Other authors declare no competing interests.