Temporal and spatial topography of cell proliferation in cancer

Abstract

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 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 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 tumor 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.

Spatial genomics maps the structure, nature and evolution of cancer clones

“…Whole-genome sequencing (WGS) analysis of the average cancer detects thousands of somatic mutations and multiple genetically related yet distinct groups of cells termed ‘subclones’ 2 , 7 , 8 . However, as genomic technologies typically assay DNA from dissociated tissues, the phenotypic consequences and the ecosystem pressures that are critical to fully understanding cancer evolution are lost 9 , 10 . Consequently, relatively little is currently known about the nature or causes of spatial patterns of cancer growth, phenotypic characteristics of distinct subclonal lineages or their interactions with tissue ecosystems 11 .…”

Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma

“…Recent advances in single-cell and multiplexed spatial analysis of tissues are driving large scale inter-institutional and international efforts to systematically characterize the spatial organization of human tumor and immune cells during cancer development and in response to therapy (Rajewsky et al, 2020;Rozenblatt-Rosen et al, 2020). Recurrent spatial features of human cancers are being identified, for example i) active immune surveillance of proliferating tumor cells by cytotoxic T cells (Gaglia et al, 2022;Launonen et al, 2022), ii) chemokineorganized tumor-immune architecture (Nirmal et al, 2022;Pelka et al, 2021), and iii) and cellcell interactions involved in generating extracellular metabolites such as adenosine, an immunosuppressive purine metabolite of ATP hydrolysis by the CD39 and CD73 ectoenzymes (Coy et al, 2022). These early insights into the tissue cellular neighborhoods and cellular architectures of human cancer tissues have revealed a pressing need for experimental and analytical approaches to investigate the mechanistic underpinnings of the anti-cancer immune response.…”

“…A value of Cxy (r) was computed for each k up to 100, and a distance r was assigned to each k as the average distance between kth nearest neighbors. More detail can be found in Gaglia et al, 2022.…”

“…FFPE sections were prepared and stained with a 24-plex antibody panel according to the previously described t-CyCIF protocols (Burger et al, 2021;Gaglia et al, 2022;Lin et al, 2018) (see Table S1). This CyCIF panel has been validated across many different sample types in accordance with standards defined by our group (Du et al, 2019).…”

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma

“…Cyclic immunofluorescence (CyCIF) 9 is one such method, enabling quantification of up to 60 antigens at single-cell resolution and generation of maps of functional neighborhoods. Integrating data from scRNA-seq and multiplexed tissue imaging has begun to reveal substantial spatial and molecular variation within human tumors 13 – 15 , and population-level regulation of tumor-immune interactions 16 . Such studies promise to reveal novel vulnerabilities in difficult to treat cancers.…”