Precancerous colorectal polyps map distinct paths to malignancy and tumor immune microenvironments.

  • Major Finding: Precancerous colorectal polyps map distinct paths to malignancy and tumor immune microenvironments.

  • Concept: Multi-omic analysis was used to develop an atlas of colorectal polyps and their cancerous counterparts.

  • Impact: The insight provided by this study can improve surveillance and prevention of colorectal cancer.

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Polyps are known precursors to colorectal cancer; however, it remains undetermined if their cellular origins, molecular heterogeneity, or immune potential reveal any diagnostic or therapeutic insight upon cancer development. Chen, Scurrah, and colleagues used a multi-omic approach on two common types of colorectal polyps, adenomas (AD) and sessile serrated lesions (SSL), collected from COLON MAP study participants, to describe two common pathways of colorectal cancer development. Cell populations were split into two distinct groups, termed AD-specific cells (ASC) and serrated-specific cells (SSC), with ASCs demonstrating similarities to colonic stem and progenitor cells and expressing genes common to WNT pathway activation, while SSCs skewed away from stem cell potential with transcriptomic profiles similar to endodermal organs, most specifically the gastric epithelium, suggesting metaplasia underlies its pathogenesis. WNT- and Hippo-driven regulons were overrepresented in ASCs, while SSCs had an observed super-regulon of interleukin signaling and microbiota interaction as well as upregulation of immunogenic state transcription factors including RELB. Colorectal cancer tumor specimens were shown to retain aspects from their precursor lesions; however, subpopulations of MSI-H (hypermutated microsatellite-instability-high) colorectal cancer cells appear to acquire stemness via non-APC WNT pathway mutations. Further evaluation of SSLs revealed an upregulation of CD8+ T cells and natural killer cells which held true in MSI-H colorectal cancers, but T-cell exhaustion signatures were observed only upon cancer development. Additionally, cytotoxic cell infiltration in SSLs preceded the hypermutation phenotype characteristic of MSI-H colorectal cancers, and colorectal cancer regions that acquired stemness were devoid of CD8+ T cells, indicating that the immune microenvironment of the tumor is dictated by degree of stemness due to cellular origins, which tracks inversely with the expression of antigen presentation machinery. Thus, this study indicates two common pathways toward colorectal cancer tumorigenesis and their distinct immune microenvironments as well as provides a path toward developing new strategies for colorectal cancer prevention and surveillance.

Chen B, Scurrah CR, McKinley ET, Simmons AJ, Ramirez-Solano MA, Zhu X, et al. Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell 2021;184:6262–80.e26.

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