Thompson Hui

Background: Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with metastatic disease accounting for the majority of CRC-related deaths.^1,2 Although surgery, chemotherapy, targeted therapy, and immunotherapy have improved survival, metastatic CRC frequently recurs or develops treatment resistance.³ Recent research suggests that these failures may be driven by cell-state plasticity, the reversible ability of tumor cells to transition between stem-like and non-stem states. In CRC, LGR5 has been a traditional marker for intestinal cancer stem cells, but emerging evidence indicates that LGR5-positive and LGR5-negative tumor states are dynamic rather than fixed.⁴ This raises an important mechanistic question: how does LGR5-associated stem cell plasticity promote metastatic colonization and resistance to therapy?

Objective: This literature review aimed to evaluate current mechanistic research on LGR5-driven plasticity in CRC and determine how these findings may inform future approaches to prognosis and treatment of metastatic disease.

Methods: PubMed and Google Scholar were searched for peer-reviewed studies published from 2020-2025 using the keywords “colorectal cancer,” “LGR5,” “cancer stem cells,” “plasticity,” “metastasis,” “therapy resistance.” Priority was given to primary mechanistic studies using patient-derived samples, organoids, lineage tracing, or in vivo metastatic models.

Results: Multiple studies support a model in which CRC progression depends on reversible transitions between LGR5-positive and LGR5-negative tumor states. Fumagalli et al. demonstrated that CRC liver metastases are often seeded by LGR5-negative cells, which later regenerate LGR5-positive cancer stem cells required for metastatic outgrowth.⁵ Moorman et al. extended this concept to human disease by showing that matched CRC metastases exhibit progressive plasticity, including fetal-like, squamous-like, and neuroendocrine-like programs associated with poor outcomes and therapeutic resistance.⁶ Heinz et al. identified YAP signaling as a temporal regulator of this process: YAP activity supports early micrometastatic survival, whereas later YAP attenuation permits re-emergence of heterogeneous stem-like states.⁷ In the therapy resistance setting, Posey et al. showed that chemotherapy or LGR5-targeted treatment can induce LGR5 loss and activate MET–STAT3 signaling, generating resistant LGR5-negative persister cells.⁸ Rio-Vilariño et al further demonstrated that AURKA-mediated YAP1 phosphorylation promotes cancer stem cell phenotypes and cetuximab resistance, while AURKA inhibition restores cetuximab sensitivity in preclinical models.⁹

Conclusion: Together, these studies shift the CRC stem cell paradigm from a fixed hierarchy to a dynamic plasticity model. LGR5-negative cells can seed metastases, LGR5-positive states can re-emerge during metastatic growth, and therapy itself can induce resistant plastic states. These findings suggest that future treatment strategies should target state transitions rather than static tumor populations. Therapeutic approaches combining standard chemotherapy or anti-EGFR therapy with inhibitors of MET–STAT3, YAP, or AURKA-mediated plasticity may help prevent metastatic outgrowth and overcome resistance. Further clinical validation is needed to determine whether plasticity biomarkers can guide prognosis and personalized therapy in metastatic CRC.

Works Cited:

1. Roshandel, G., Ghasemi-Kebria, F., & Malekzadeh, R. (2024). Colorectal Cancer: Epidemiology, Risk Factors, and Prevention. Cancers, 16(8), 1530. https://doi.org/10.3390/cancers16081530
2. Siegel, R. L., Wagle, N. S., Cercek, A., Smith, R. A., & Jemal, A. (2023). Colorectal cancer statistics, 2023. CA: A Cancer Journal for Clinicians, 73(3), 233–254. https://doi.org/10.3322/caac.21772
3. Cañellas-Socias, A., Sancho, E., & Batlle, E. (2024). Mechanisms of metastatic colorectal cancer. Nature Reviews Gastroenterology & Hepatology, 21(9), 609–625. https://doi.org/10.1038/s41575-024-00934-z
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7. Heinz, M. C., Peters, N. A., Oost, K. C., Lindeboom, R. G. H., van Voorthuijsen, L., Fumagalli, A., van der Net, M. C., de Medeiros, G., Hageman, J. H., Verlaan-Klink, I., Borel Rinkes, I. H. M., Liberali, P., Gloerich, M., van Rheenen, J., Vermeulen, M., Kranenburg, O., & Snippert, H. J. G. (2022). Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage. Cancer Research, 82(10), 1953–1968. https://doi.org/10.1158/0008-5472.CAN-21-0933
8. Posey, T. A., Jacob, J., Parkhurst, A., Subramanian, S., Francisco, L. E., Liang, Z., & Carmon, K. S. (2023). Loss of LGR5 through Therapy-induced Downregulation or Gene Ablation Is Associated with Resistance and Enhanced MET-STAT3 Signaling in Colorectal Cancer Cells. Molecular Cancer Therapeutics, 22(5), 667–678. https://doi.org/10.1158/1535-7163.MCT-22-0415
9. Rio-Vilariño, A., Cenigaonandia-Campillo, A., García-Bautista, A., Mateos-Gómez, P. A., Schlaepfer, M. I., del Puerto-Nevado, L., Aguilera, O., García-García, L., Galeano, C., de Miguel, I., Serrano-López, J., Baños, N., Fernández-Aceñero, M. J., Lacal, J. C., Medico, E., García-Foncillas, J., & Cebrián, A. (2024). Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells. British Journal of Cancer, 130(8), 1402–1413. https://doi.org/10.1038/s41416-024-02649-z