A new study published in Nature has identified TROP2 as a marker of aggressive colorectal cancer cell populations associated with metastasis, treatment resistance, and poor clinical outcomes.
Title: “TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer”
Authors: Nuria Vaquero-Siguero, Nikolaos Georgakopoulos, Maria C. Puschhof, Ioannis Chiotakakos, Jasmin Meier, Sigrid K. Fey, Gabriele Diamante, Manuel Mastel, Aitana Guiseris-Martinez, Guillaume Belthier, Nikolai Schleußner, Julia Volk, Carolin Artmann, Bryce Lim, Ronald Koschny, Cyrill Wehling, Kyanna S. Ouyang, Michael Günther, Solveig Kuss, Paula Hoffmeister, Moritz Mall, Jens Neumann, Steffen Ormanns, Martin Schneider, Rene Jackstadt
The findings suggest that colorectal cancer cells can shift between distinct cellular states during treatment, creating a potential therapeutic opportunity: combining standard chemotherapy with TROP2-directed antibody–drug conjugates.
The research, led by investigators from the German Cancer Research Center and collaborating institutions, examined human colorectal cancer samples, patient-derived organoids, xenograft models, and genetically engineered mouse models to better understand how tumour cell plasticity contributes to disease progression.
A Marker of Poor-Prognosis Colorectal Cancer
Metastatic colorectal cancer remains difficult to treat, particularly in microsatellite-stable disease, where chemotherapy combinations such as FOLFOX and FOLFIRI remain central components of care.
However, tumour cells do not remain static during therapy. They can adapt, alter their gene-expression programs, and acquire characteristics that support survival, metastatic spread, and resistance to treatment.
In the new study, researchers identified trophoblast cell-surface antigen 2, known as TROP2, as a marker of colorectal cancer cells with features associated with poor prognosis.
High TROP2 expression was linked to distant metastasis in a case-control cohort of patients with colorectal cancer. TROP2 expression was observed in 37.8% of metastatic tumours, compared with 17.1% of non-metastatic tumours.
Across 16 publicly available colorectal cancer datasets involving 1,336 patients, high TROP2 expression was also associated with shorter relapse-free survival.
The researchers found that TROP2 was particularly associated with tumour states marked by low WNT signalling and fetal-like cellular programs. These states have previously been linked to aggressive tumour behaviour, metastatic progression, and resistance to systemic therapy.
TROP2 and LGR5 Mark Different Tumour Cell States
Cancer stem cells are thought to play an important role in colorectal cancer growth, recurrence, and metastatic spread. For years, LGR5 has been considered one of the major markers of colorectal cancer stem cells.
The new findings suggest that this model may be incomplete.
Researchers observed that TROP2-positive and LGR5-positive tumour cells largely represented distinct populations. LGR5-positive cells were more prominent in WNT-high colorectal cancers, while TROP2-positive cells appeared to play a more important role in WNT-low tumours.
In WNT-low colorectal cancer models, TROP2-positive cells demonstrated enhanced tumour-initiating capacity and stem-like behaviour. These cells were also capable of restoring the broader tumour cell population over time, highlighting the high degree of plasticity within colorectal cancer.
This distinction may be clinically important. While LGR5-positive cells have traditionally been associated with colorectal cancer stemness, TROP2-positive cells may represent an alternative stem-like population in tumours where WNT signalling is lower.
A Role in Metastatic Seeding
The study also examined how TROP2-positive cells behave during metastatic spread.
TROP2 expression was detected early during metastatic seeding, including in micro-metastatic lesions. By contrast, LGR5 expression was more prominent in larger metastatic lesions.
In experimental models, TROP2-positive cells showed a greater ability to initiate metastatic outgrowth than TROP2-negative cells. This was observed across different molecular contexts, suggesting that TROP2 may identify a population of cells particularly equipped to survive the early stages of metastasis.
These findings position TROP2 not only as a marker of therapy-resistant disease, but also as a potential marker of metastasis-initiating cells.
Chemotherapy Can Increase TROP2 Expression
One of the most striking observations from the study was the effect of chemotherapy on tumour cell states.
Treatment with FOLFIRI increased TROP2 expression across multiple patient-derived colorectal cancer organoid models, regardless of baseline TROP2 levels. The increase was accompanied by a reduction in LGR5 expression and a shift toward fetal-like tumour programs.
Importantly, this TROP2 induction appeared reversible after chemotherapy was withdrawn, underscoring the dynamic nature of colorectal cancer cell populations.
The researchers found that chemotherapy did not merely select pre-existing TROP2-positive cells. Instead, treatment appeared to induce a broader transition toward a TROP2-high state.
This suggests that chemotherapy may reshape the tumour landscape, potentially creating a treatment window in which TROP2-directed therapies could become more effective.
Targeting TROP2 With Antibody–Drug Conjugates
TROP2-directed antibody–drug conjugates have already gained attention in other malignancies, particularly breast cancer. These therapies use an antibody to recognize TROP2-expressing cells and deliver a cytotoxic payload directly to the tumour.
In this study, researchers evaluated sacituzumab govitecan and sacituzumab tirumotecan in patient-derived colorectal cancer models.
Sacituzumab govitecan demonstrated greater activity in tumours with higher TROP2 expression. Treatment reduced TROP2-positive cell populations and altered the composition of tumour cell states.
Following TROP2-directed treatment, tumours showed a decline in fetal-like and high-relapse cell programs, alongside an increase in LGR5-associated intestinal stem cell signatures.
This shift was not permanent. When drug pressure decreased, TROP2-positive and fetal-like cell states could re-emerge, again demonstrating the adaptability of colorectal cancer cells.
Combining Chemotherapy and TROP2 Targeting
Because chemotherapy increased TROP2 expression, the investigators explored whether chemotherapy could be paired with TROP2-directed treatment.
In patient-derived and metastatic colorectal cancer models, combining FOLFOX or FOLFIRI-based approaches with TROP2-directed antibody–drug conjugates produced stronger anti-tumour effects than either strategy alone.
The combination approach was active in both early metastatic disease models and established metastatic lesions. The findings support a treatment concept in which chemotherapy and TROP2-targeted therapy act on different tumour cell states.
Chemotherapy may preferentially affect LGR5-positive, WNT-high tumour cells while simultaneously pushing some cancer cells toward a TROP2-positive state. TROP2-directed antibody–drug conjugates may then target this treatment-induced population.
From Biological Insight to Clinical Investigation
The results provide a detailed look at how colorectal cancer cells adapt during therapy and how those adaptations may be therapeutically exploited.
However, the findings remain preclinical. The work was conducted using patient-derived organoids, xenografts, mouse models, and analyses of human tumour datasets. Clinical trials will be needed to determine whether TROP2 expression can guide treatment decisions in patients with colorectal cancer and whether chemotherapy-TROP2 targeting combinations can improve outcomes in the clinic.
The study also raises important questions about biomarker development. Because TROP2 expression appears dynamic and treatment-dependent, a single baseline tumour sample may not fully capture the target’s relevance throughout a patient’s treatment course.
For advanced colorectal cancer, where therapy resistance and metastatic progression remain major barriers, the ability to target changing tumour cell states may represent an important direction for future research.
Written by Nare Hovhannisyan, MD
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