This study systematically reveals the close association between TROP2+ cell states and chemotherapy resistance and metastasis in colorectal cancer, providing direct experimental evidence for developing combination therapies based on cell state transitions. It suggests that TROP2 could serve as a key node for dynamic monitoring and intervention.
Literature Overview
The paper titled 'TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer,' published in the journal Nature, systematically investigates the functional role of TROP2 as a poor prognostic marker in colorectal cancer and its dynamic changes during therapy response. By integrating single-cell transcriptomics, patient-derived organoids, and multiple genetically engineered mouse models, the study reveals that TROP2+ cells exhibit stem-like properties in a low-WNT signaling context and mediate metastasis and drug resistance. Using a TROP2 antibody–drug conjugate (ADC), the authors demonstrate that targeting TROP2 can reshape tumor cell states and enhance the efficacy of chemotherapy. The research highlights the critical role of cellular plasticity under therapeutic pressure, offering new strategies to overcome resistance.Background Knowledge
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with high mortality primarily attributed to metastasis and systemic therapy resistance. The current standard treatment for microsatellite stable CRC involves 5-FU–based chemotherapy regimens such as FOLFIRI or FOLFOX, but these offer limited efficacy, with only a 12% five-year survival rate for advanced patients. Recently, tumor cell plasticity has been recognized as a core mechanism underlying resistance and metastasis. The traditional cancer stem cell marker LGR5, highly expressed in adult intestinal stem cells, is downregulated in metastatic and therapy-resistant cells, replaced instead by cells exhibiting fetal-like or high recurrence-associated (HRC) states. These states are often associated with low WNT pathway activity and are found in poor-prognosis subtypes such as CMS4 and iCMS3. However, effectively targeting these dynamically shifting cell states remains a clinical challenge. TROP2 (encoded by TACSTD2), a transmembrane glycoprotein highly expressed in various epithelial cancers but minimally in most normal tissues, represents a potential therapeutic target. Although TROP2-ADCs such as sacituzumab govitecan have been approved for triple-negative breast cancer, their functional roles and relationship with cell state dynamics in colorectal cancer remain unclear. This study addresses this unmet clinical need by systematically dissecting the role of TROP2 in CRC progression and therapy response, filling a critical gap in targeting cell state plasticity.
Research Methods and Experiments
The authors first integrated transcriptomic data from 16 public cohorts (n=1336), along with TCGA and in-house cohorts, confirming that high TROP2 expression is significantly associated with shorter recurrence-free survival. Using single-cell RNA sequencing (scRNA-seq) on patient primary and liver metastatic samples, they found TROP2 primarily enriched in fetal-like and HRC cell clusters, with mutually exclusive expression relative to LGR5, suggesting a duality of these two cell states. For functional validation, the team generated multiple genetically engineered mouse models (GEMMs), including classical adenoma-carcinoma and serrated pathway models. Flow cytometry and organoid formation assays demonstrated that TROP2 expression increases with tumor malignancy and that TROP2+ cells possess greater sphere-forming capacity. In vivo, limiting dilution transplantation experiments revealed that TROP2+ cells have higher tumor-initiating capacity in low-WNT signaling models but not in high-WNT models, indicating that TROP2's stemness is dependent on WNT signaling status. Furthermore, using an Lgr5-tdTomato mouse model, they confirmed that LGR5 exhibits stemness function only in high-WNT models with Apc loss.
To explore the therapeutic potential of TROP2 targeting, the authors treated patient-derived organoids (PDOs) and patient-derived organoid xenografts (PDOX) with a TROP2-ADC (SG). Results showed that SG treatment significantly prolonged survival in high-TROP2-expressing models and reduced the proportion of TROP2+ cells. Single-cell transcriptomic analysis revealed that post-SG treatment, tumor cell states shifted toward LGR5+ and intestinal stem cell (ISC)–like states, marked by activation of the WNT signaling pathway. Time-series experiments further showed that cell state reprogramming occurred within 48 hours of a single SG dose. To simulate clinical treatment, the authors evaluated the impact of chemotherapy (FOLFIRI) on TROP2 expression and found that chemotherapy induces TROP2 expression—a reversible process—indicating that chemotherapy promotes expansion of TROP2+ cells via therapy-driven cell state transitions. Finally, combining chemotherapy with SG treatment significantly enhanced antitumor efficacy in PDOX models, especially in early metastasis models, suggesting that sequential or combinatorial targeting can overcome resistance.Key Conclusions and Perspectives
Research Significance and Prospects
This study fundamentally shifts the understanding of therapy resistance in colorectal cancer—from a static view based on genetic mutations to a dynamic perspective centered on cell state plasticity. TROP2 is not merely a surface target but a hub for cell fate transitions, with its expression regulated by therapeutic pressure. This finding emphasizes that drug development must consider the impact of therapies on the entire landscape of cell states, rather than focusing solely on killing efficiency. For clinical monitoring, TROP2 expression levels could serve as a dynamic biomarker to guide treatment selection and timing. For example, an increase in TROP2 after chemotherapy might indicate a window for initiating ADC intervention. In disease modeling, the GEMMs and PDOX models established in this study provide ideal platforms for testing novel drugs targeting cellular plasticity. Moreover, this mechanism may extend to other epithelial cancers, broadening the applicability of TROP2-ADCs.
Conclusion
This study establishes TROP2 as a key mediator of therapy-induced cell state plasticity and a promising therapeutic target in colorectal cancer. Under chemotherapy pressure, tumor cells achieve immune evasion and resistance by transitioning into TROP2+, fetal-like states. TROP2-ADCs not only eliminate these resistant clones but also actively reprogram cell fate, reverting cells to a chemotherapy-sensitive state. This 'induce-then-eliminate' combination strategy precisely exploits the adaptive vulnerabilities of tumors, representing a paradigm shift from passively responding to resistance to actively manipulating cell fate. From bench to bedside, this research offers new therapeutic avenues for patients with advanced colorectal cancer, underscores the importance of dynamically monitoring TROP2 status, and lays the foundation for next-generation precision therapies based on cell states. Future studies should focus on the upstream regulatory mechanisms of TROP2 state transitions and explore its universality across other cancer types, further advancing personalized medicine.
