Montero-Calle Ana, Jiménez de Ocaña Sofía, Rejas-González Raquel, Benavente-Naranjo Ruth, Sanz-López Rodrigo, Dziaková Jana, Martínez-Useros Javier, Peláez-García Alberto, de Los Ríos Vivian, Bartolomé Rubén A, Casal J Ignacio, Fernández-Aceñero María Jesús, Barderas Rodrigo
Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, Madrid, Spain.
Proteomics Core, UCCTs, Instituto de Salud Carlos III, Madrid, Spain.
Br J Cancer. 2025 Sep 17. doi: 10.1038/s41416-025-03184-1.
Tropomodulin-2 (TMOD2) is upregulated in the nuclear compartment of highly liver metastatic colorectal cancer (CRC) cells. Its role in cancer and CRC progression is functionally undefined, despite its analysis in COAD and READ TCGA datasets revealing a correlation between high TMOD2 expression, advanced disease stages, and poorer survival in CRC patients. We aimed here to explore the role of TMOD2 in CRC and liver metastasis using functional proteomics, tumour samples, bioinformatics, and in vitro and in vivo CRC models. Stable overexpression and stable depletion of TMOD2 in isogenic CRC cells revealed its impact on tumorigenic and metastatic properties. TMOD2 overexpression enhanced cell adhesion, anchorage-independent growth, and migration, while stably TMOD2 depletion reduced them. In vivo, TMOD2-overexpressing cells formed larger tumours and enhanced liver colonisation of CRC cells. Clinically, TMOD2 protein levels demonstrated strong discriminatory ability between metastatic and non-metastatic CRC patients. Proteomic analyses allowed the identification of TMOD2-associated proteins involved in cytoskeletal dynamics, secretion, and focal adhesions, with further validation implicating STAG1 and MARCKS as mediators of TMOD2-driven pathways. Our findings demonstrate that TMOD2 plays a role in CRC progression by modulating cytoskeletal dynamics, enhancing cell adhesion and promoting liver metastasis, positioning TMOD2 as a target for therapeutic intervention in CRC.
原肌球蛋白-2（TMOD2）在高肝转移潜能的结直肠癌（CRC）细胞核区室中表达上调。尽管对COAD和READ的TCGA数据集分析显示，高TMOD2表达与CRC患者疾病进展晚期及较差的生存率相关，但其在癌症及CRC进展中的作用在功能上仍不明确。我们旨在通过功能蛋白质组学、肿瘤样本、生物信息学以及体外和体内CRC模型，探究TMOD2在CRC和肝转移中的作用。在同基因CRC细胞中稳定过表达和稳定敲低TMOD2，揭示了其对致瘤和转移特性的影响。TMOD2过表达增强了细胞黏附、非锚定依赖性生长和迁移能力，而稳定敲低TMOD2则降低了这些能力。在体内，过表达TMOD2的细胞形成了更大的肿瘤，并增强了CRC细胞在肝脏的定植。临床上，TMOD2蛋白水平在转移性和非转移性CRC患者之间表现出很强的鉴别能力。蛋白质组学分析鉴定出了与TMOD2相关的、参与细胞骨架动力学、分泌和黏着斑的蛋白质，进一步验证表明STAG1和MARCKS是TMOD2驱动通路的介质。我们的研究结果表明，TMOD2通过调节细胞骨架动力学、增强细胞黏附以及促进肝转移，在CRC进展中发挥作用，这使TMOD2成为CRC治疗干预的一个靶点。
