Dander Erica, Pischiutta Francesca, Di Marzo Noemi, Pascente Rosaria, Panini Nicolò, Fallati Alessandra, Biondi Andrea, Zanier Elisa R, D'Amico Giovanna
Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, via Pergolesi 33, Monza, MB, 20900, Italy.
Departement of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Sci Rep. 2025 May 29;15(1):18915. doi: 10.1038/s41598-025-03877-w.
B-cell type acute lymphoblastic leukemia (B-ALL) is the most common type of childhood malignancy. Although the survival rate nowadays exceeds 90%, central nervous system (CNS) involvement is associated with a poor outcome. Experimental models are needed to study the interaction between leukemia cells and the brain microenvironment to unravel new targets for drug intervention. We developed a novel three-dimensional (3D) ex vivo model utilizing murine organotypic cortical brain slices microinjected with human B-ALL cells, serving as a platform for investigating the influence of Activin A, a pro-leukemic factor, on leukemia invasion into the CNS. After injection, B-ALL cells exponentially increased in the cortical slices, promoting tissue mortality and an anti-inflammatory microenvironment phenotype, as demonstrated by morphological and gene expression alterations in microglia and astrocytes. Of note, Activin A pretreatment increased leukemia proliferation and exacerbated the effects on the microenvironment. Overall, our model presents an ideal platform for investigating the cross-talk between tumors and the brain microenvironment and the influence of disease-modifying factors. Moreover, it could facilitate drug screening across a spectrum of CNS cancers, meanwhile reducing animal usage.
B细胞型急性淋巴细胞白血病（B-ALL）是儿童期最常见的恶性肿瘤类型。尽管如今生存率超过90%，但中枢神经系统（CNS）受累与不良预后相关。需要实验模型来研究白血病细胞与脑微环境之间的相互作用，以揭示药物干预的新靶点。我们开发了一种新型三维（3D）体外模型，利用微注射了人B-ALL细胞的小鼠脑皮质器官型切片，作为研究促白血病因子激活素A对白血病侵袭中枢神经系统影响的平台。注射后，B-ALL细胞在皮质切片中呈指数增长，促进组织死亡和抗炎微环境表型，这通过小胶质细胞和星形胶质细胞的形态学和基因表达改变得以证明。值得注意的是，激活素A预处理增加了白血病增殖，并加剧了对微环境的影响。总体而言，我们的模型为研究肿瘤与脑微环境之间的相互作用以及疾病修饰因子的影响提供了理想平台。此外，它可以促进对一系列中枢神经系统癌症的药物筛选，同时减少动物使用量。
