TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer
Menée à l'aide de modèles murins, d'organoïdes ainsi que d'échantillons de tumeurs et de muqueuses colorectales saines d'origine humaine, cette étude identifie la glycoprotéine transmembranaire TROP2 comme un marqueur de mauvais pronostic, démontre que les cellules qui l'expriment possèdent des propriétés de cellules souches et ont la capacité d'initier la formation de métastases puis met en évidence l'intérêt de cibler TROP-2 pour améliorer l'efficacité anti-tumorale de la chimiothérapie
Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity1. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNTlow, fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2+ cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody–drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell state composition between WNThi LGR5+ states and WNTlowTROP2+ fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2 antibody–drug conjugates selectively target these populations and remodel the tumour cell state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.
Nature , article en libre accès, 2026