Temporal and spatial topography of cell proliferation in cancer

Giorgio Gaglia, Sheheryar Kabraji, Danae Rammos, Yang Dai, Ana Verma, Shu Wang, Caitlin E. Mills, Mirra Chung, Johann S. Bergholz, Shannon Coy, Jia-Ren Lin, Rinath Jeselsohn, Otto Metzger, Eric P. Winer, Deborah A. Dillon, Jean J. Zhao, Peter K. Sorger & Sandro Santagata

Nature Cell Biology. 2022 Mar; 24(3): 316-326. PMID: 35292783. PMCID: PMC8959396.

Proliferation is a fundamental trait of cancer cells but its properties and spatial organization in tumors are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and develop robust, multivariate, proliferation metrics. Across diverse cancers, the proliferative architecture is organized at two spatial scales: large domains, and local niches enriched for specific immune lineages. Some tumor 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 tumor cell populations are skewed toward 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 behavior. 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.