Triulzi Tiziana, Giussani Marta, Maffioli Elisa, Regondi Viola, Lorenc Ewelina J, Arlotta Valeria, Bianchi Francesca, Pozzi Sabina, Varricchio Martina, Cancila Valeria, Valenti Cesare, Sandri Marco, Podestà Alessandro, Sfondrini Lucia, Vozzi Giovanni, Tedeschi Gabriella, Pupa Serenella M, Tagliabue Elda
Microenvironment and Biomarkers of Solid Tumors Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Department of Veterinary Medicine and Animal Science, Università degli Studi di Milano, Milan, Italy.
NPJ Breast Cancer. 2025 Jun 6;11(1):51. doi: 10.1038/s41523-025-00769-0.
An extracellular matrix (ECM) gene expression pattern (ECM3) distinguished truly aggressive grade III breast carcinomas (BCs). Here, we examined the biomechanical characteristics of the ECM in human BCs to identify the molecules that mediate the aggressiveness of ECM3/grade III (E3G3) tumors. By shotgun proteomics of decellularized human BCs, we found a significant enrichment in proteins involved in tumor-ECM interaction in E3G3 tumors. These tumors were characterized by high dense collagen deposition, a fibrillary cytoskeleton network and the highest stiffness. CLEC3A, a secreted C-type lectin domain family 3 member, was found unique of E3G3 tumors and was validated to be more expressed in these tumors by immunohistochemistry in 2 human BC cohorts, associating significantly with worse prognosis. Ectopic CLEC3A overexpression in MDA-MB-231, MDA-MB-361, and MDA-MB-468 BC cells increased intracellular mediators of tumor adhesion to the ECM, actin-stress fibers and YAP activation, and tumor migration. Accordingly, levels of the YAP/TAZ gene signature were higher in CLEC3A-positive ECM3-enriched tumors and correlated with tumor stiffness. These results implicate CLEC3A in mediating the ability of E3G3 BCs to sense cues in the surrounding ECM, accelerating tumor progression.
一种细胞外基质（ECM）基因表达模式（ECM3）可区分真正具有侵袭性的III级乳腺癌（BC）。在此，我们研究了人类乳腺癌中ECM的生物力学特征，以确定介导ECM3/III级（E3G3）肿瘤侵袭性的分子。通过对脱细胞人乳腺癌进行鸟枪法蛋白质组学分析，我们发现E3G3肿瘤中参与肿瘤-ECM相互作用的蛋白质显著富集。这些肿瘤的特征是高密度胶原沉积、纤维状细胞骨架网络和最高的硬度。CLEC3A是分泌型C型凝集素结构域家族3成员，被发现是E3G3肿瘤所特有的，并且通过免疫组织化学在2个人类乳腺癌队列中验证其在这些肿瘤中表达更高，与更差的预后显著相关。在MDA-MB-231、MDA-MB-361和MDA-MB-468乳腺癌细胞中异位过表达CLEC3A可增加肿瘤与ECM粘附的细胞内介质、肌动蛋白应激纤维和YAP激活以及肿瘤迁移。因此，YAP/TAZ基因特征水平在CLEC3A阳性的富含ECM3的肿瘤中更高，并且与肿瘤硬度相关。这些结果表明CLEC3A在介导E3G3乳腺癌感知周围ECM中的信号、加速肿瘤进展的能力中发挥作用。
