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Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2IEC-Tg/+) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development. Zeb2IEC-Tg/+ mice develop a dysplastic colonic epithelium, which progresses to severely inflamed neoplastic lesions while the small intestinal epithelium remains normal. Zeb2IEC-Tg/+ mice are characterized by intestinal dysbiosis, and microbiota depletion with broad-spectrum antibiotics or germ-free rederivation completely prevents cancer development. Zeb2IEC-Tg/+ mice represent the first mouse model of spontaneous microbiota-dependent invasive CRC and will help us to better understand host–microbiome interactions driving CRC development in humans. Van Loo and colleagues report that loss of the Zeb2 regulator of epithelial-to-mesenchymal transition from the intestinal epithelium leads to inflammation, increased intestinal permeability and colorectal cancer development, which is enhanced by the resident intestinal microbiome.

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.

The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4+ T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers. ispartof: CELL RESEARCH vol:30 issue:9 pages:745-762 ispartof: location:England status: published

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3601 Background: High stromal content (CMS4) and immune infiltration (CMS1) are important features of the tumor micro-environment (TME) in early stage colorectal cancer, with poor and good RFS prognosis, respectively. However, it remains unclear how these TME features are influenced by intrinsic tumor epithelial expression profiles. We examined how the former can be predicted by the latter, and assessed their respective prognostic contributions. Methods: Eighteen public gene-expression datasets (n=3511) were used for discovery, and an adjuvant trial dataset (PETACC3 n=688) was used for validation. Whole-transcriptome hierarchical clustering was applied to identify intrinsic versus extrinsic co-expression modules, corroborated by single-cell profiling data. The epithelial gene subset were used to predict previously assigned CMS labels, producing new CRC classifier that we refer to as epithelial-CMS (eCMS). Results: Despite lacking stromal and immune response genes, eCMS predicted CMS with an accuracy of 82% [CI 78-85%] in the test dataset. Not only were the RFS prognostic values retained (eCMS1 vs non-eCMS1: HR=0.59 [CI 0.35–0.95, p=0.029], and eCMS4 vs non-e-CMS4: HR=1.82 [CI 1.38–2.41, p=0.0003]), but they were also significantly improved when compared to the original CMS classification (CMS1 vs non-CMS1: HR=0.76 [CI 0.49–1.16, p=0.2] and CMS4 vs non-CMS4: HR=1.43 [CI 1.07–1.91, p=0.017]. In a multivariable regression comparison, eCMS was superior to CMS (p=0.001 vs p=0.36). Each eCMS group was associated with specific combinations of up- and down-regulation of CRC-relevant pathways, such as CDX2, map-kinase, mucin secretion, DNA damage repair and cell proliferation. Conclusions: Stromal and immune infiltration patterns in the TME are strongly associated with tumor epithelial expression profiles, as captured by eCMS. This finding sheds new light on the interplay between intrinsic molecular features of CRCs and their TME, and illuminates new paths for potential combination therapies.