Leedham, S. | bioRxiv Science

bioRxiv2019

Niche engineering drives early passage through an immune bottleneck in progression to colorectal cancer

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/623959v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (55K):\norg.highwire.dtl.DTLVardef@1c48cf5org.highwire.dtl.DTLVardef@1026747org.highwire.dtl.DTLVardef@ca92f1org.highwire.dtl.DTLVardef@1753cd5_HPS_FORMAT_FIGEXP M_FIG C_FIG Colorectal cancer develops from its precursor lesion, the adenoma. The immune system is hypothesized to be key in modulating progression, but tumor-immune eco-evolutionary dynamics remain uncharacterized. Here, we demonstrate a key role for immune evasion in the progression of human benign disease to colorectal cancer. We constructed a mathematical model of tumor-immune eco-evolutionary dynamics that predicted ecological succession, from an \"immune-hot\" adenoma immune ecology rich in T cells to an \"immune-cold\" carcinoma ecology, deficient in T cells and rich in immunosuppressive cells. Using a cross-sectional cohort of adenomas and carcinomas, we validated this prediction by direct measurement of the tumor-immune ecology using whole-slide 10-marker immunohistochemistry (IHC), and analysis of neoantigen clonal architecture multi-region exome sequencing data. Changes in immune ecology relax selection against antigens with high recognition potentials. This study indicates that immune surveillance represents a key evolutionary bottleneck in the evolution of colon cancer.

cancer biology↗

bioRxiv2019

Clonal Architecture of the Epidermis: Homeostasis Limits Keratinocyte Evolution

The skin is the largest human organ, functioning to serve as the protective barrier to the harsh, outside world. Recent studies have revealed that large numbers of somatic mutations accumulate in normal tissue, which can be used to infer skin cell dynamics1-5. Here we present the first realistic, cell-genome mechanistic epidermal model that shows homeostasis imposes a characteristic log-linear subclone size distribution for both neutral and oncogenic driver mutations, where the largest skin subclones are the oldest subclones. Because homeostasis inherently limits proliferation and therefore clonal sweeps, selection for driver mutations (NOTCH1 and TP53) in normal epidermis is instead conferred by greater persistence, which leads to larger subclone sizes. These results highlight how the integration of mechanistic modeling with genomic data provide novel insights into the evolutionary cell dynamics of normal human homeostatic tissues.

evolutionary biology↗