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Cancer stem cells (CSCs) are a long‐lived and self‐renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5 + CSCs as well as quiescent Lgr5 + CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57 + cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57 + cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57 + cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts. Rapid turnover and regeneration of intestinal epithelium requires distinct intestinal stem cell (ISC) populations. Here the authors show p57 marks quiescent ISCs, and that differentiated cells revert to stem cell state after injury, through dynamic reprogramming characterized by fetal- and metaplastic-like changes.

The tumor immune microenvironment plays a key role in the regulation of cancer progression. Recent studies have suggested a relation between diverse tumor genotypes and tumor immune microenvironment phenotypes for cholangiocarcinoma (CCA). However, the contribution of tumor‐infiltrating immune cells to CCA progression has remained unclear, underscoring the need for genetically defined CCA models in immunocompetent mice. We here aimed to generate genetically engineered and transplantable CCA organoids from C57BL/6 mice and to investigate the role of tumor‐infiltrating immune cells in CCA progression with this model. CCA organoids were generated ex vivo with the use of the CRISPR/Cas9 system. Orthotopic transplantation of CCA organoids harboring mutations in Smad4, Trp53, and Kras into wild‐type C57BL/6 mice resulted in tumor formation accompanied by distant metastasis. Selective depletion of immune cell types in the tumor‐bearing mice revealed an antitumor action of tumor‐infiltrating neutrophils (TINs) that was mediated by direct killing of cancer cells through the production of reactive oxygen species. Furthermore, administration of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) increased the number and cytotoxicity of TINs, suppressed tumor growth, and prolonged the survival of tumor‐bearing mice. Finally, combination treatment with rhG‐CSF and standard chemotherapy resulted in a synergistic attenuation of tumor growth. Our study therefore provides a syngeneic and genetically defined mouse model of CCA and highlights the therapeutic potential of targeting TINs with rhG‐CSF. This study developed a genetically engineered and transplantable cholangiocarcinoma (CCA) organoid model in immunocompetent mice to investigate the role of tumor‐infiltrating immune cells in CCA progression. The findings revealed that tumor‐infiltrating neutrophils (TINs) exhibit antitumor activity by directly killing cancer cells through reactive oxygen species, and their effects were enhanced by recombinant human granulocyte colony‐stimulating factor (rhG‐CSF), which suppressed tumor growth and improved survival. Additionally, combining rhG‐CSF with standard chemotherapy showed synergistic tumor suppression, highlighting the therapeutic potential of targeting TINs in CCA.