TROP2靶向揭示结直肠癌中治疗驱动的细胞状态动力学，这一成果由海德堡干细胞技术与实验医学研究所Rene Jackstadt小组经过不懈努力而取得。该研究于2026年7月1日发表于国际一流学术期刊《自然》杂志上。

在这里，该研究团队发现跨膜糖蛋白滋养细胞表面抗原2 （TROP2）是与WNT^low相关的不良预后结直肠癌（CRC）的标志物，WNT^low是与转移和治疗耐药性相关的胎儿样肿瘤细胞状态。功能分析表明，TROP2⁺细胞表现出上下文依赖的干细胞样能力和启动转移性生长的能力。鉴于这些有害的肿瘤状态集中在细胞表面抗原TROP2上，该研究团队探索了这种细胞群体的治疗靶向性，主题是临床相关的TROP2导向的抗体-药物偶联物。

时间分辨分析揭示了肿瘤细胞状态组成在WNThi LGR5⁺状态和WNT^lowTROP2⁺胎儿样状态之间的治疗相关动态。传统化疗促进了TROP2表达细胞的诱导，而TROP2抗体-药物偶联物选择性地靶向这些细胞群并重塑肿瘤细胞状态景观。利用这种可塑性，联合化疗和TROP2靶向增强了患者源性模型的抗肿瘤疗效。总之，他们的发现确定了TROP2是CRC的治疗易感点，并强调了靶向肿瘤细胞状态以提高晚期疾病的治疗效果和克服耐药性的重要性。

据介绍，转移仍然是癌症相关死亡的主要原因，并且是由肿瘤细胞明显的可塑性所驱动的。

附：英文原文

Title: TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer

Author: Vaquero-Siguero, Nuria, Georgakopoulos, Nikolaos, Puschhof, Maria C., Chiotakakos, Ioannis, Meier, Jasmin, Fey, Sigrid K., Diamante, Gabriele, Mastel, Manuel, Guiseris-Martinez, Aitana, Belthier, Guillaume, Schleuner, Nikolai, Volk, Julia, Artmann, Carolin, Lim, Bryce, Koschny, Ronald, Wehling, Cyrill, Ouyang, Kyanna S., Gnther, Michael, Kuss, Solveig, Hoffmeister, Paula, Mall, Moritz, Neumann, Jens, Ormanns, Steffen, Schneider, Martin, Schmidt, Thomas, Puschhof, Jens, Trumpp, Andreas, van Rheenen, Jacco, Saez-Rodriguez, Julio, Khler, Bruno C., Jackstadt, Rene

Issue&Volume: 2026-07-01

Abstract: 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.

DOI: 10.1038/s41586-026-10705-2

Source: https://www.nature.com/articles/s41586-026-10705-2