Cell Adhesion Signaling Regulates Cancer Stem Cell Dormancy after Chemotherapy

Drug resistance leading to cancer relapse continues to pose a major issue in cancer-related deaths. One hypothesis is that this phenotype is mediated by cancer stem cells (CSC); however, this has not been experimentally tested due to a lack of genetic tracing approaches that provide spatiotemporal resolution. Ohta, Fujii, and colleagues developed a 4D, ex vivo live imaging system that demonstrated a critical role for dormant LGR5⁺ p27⁺ colorectal CSCs in postchemotherapy tumor regrowth. Chemotherapy was found to enrich this particular cell population, as intravital tracing of LGR5 in organoid xenografts showed these double-positive cells remained after chemotherapy treatment and clonally expanded after treatment, suggesting their ability to contribute to tumor regrowth after drug cessation. Maintenance of these LGR5⁺ p27⁺ cells was supported by cell–matrix interactions, and gene ontology analysis showed upregulation of COL17A1, a hemidesmosome structural component that supports epithelial cell adhesion to the basement membrane. Functionally, COL17A1 maintains CSC dormancy, as COL17A1 knockout led to increased proliferation as well as enhanced susceptibility to chemotherapy, with additional studies indicating activation of the FAK–YAP signaling pathway upon COL17A1 loss. To investigate the effects of FAK–YAP activation on the dormant cell state, YAP was pharmacologically inhibited through use of a TEAD inhibitor following COL17A1 knockout, which resulted in the reappearance of p27⁺ cells as well as inhibition of these cells reentering the cell cycle. Furthermore, chemotherapy treatment disrupted COL17A1 expression leading to dormancy abrogation through activation of FAK-YAP, while treatment with an inhibitor of YAP activity blocked postchemotherapy regrowth, supporting the role of this pathway in promoting cell cycle reentry as well as suggesting that targeting this pathway can break dormancy and prevent cancer relapse. In summary, this study identified dormant CSC populations in human colorectal cancer as well as a pathway that maintains this phenotype, indicating that its disruption could curb tumor regrowth after chemotherapy.

Ohta Y, Fujii M, Takahashi S, Takano A, Nanki K, Matano M, et al. Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature 2022 Jul 7 [Epub ahead of print].

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