Israeli Dangoor Sahar, Khoury Rami, Salomon Koren, Pozzi Sabina, Shahar Shir, Miari Adan, Leichtmann-Bardoogo Yael, Bar-Hai Neta, Frommer Neta, Yeini Eilam, Winkler Tom, Balint Lahat Nora, Kamer Iris, Hadad Ori, Laue Kathrin, Brem Henry, Hyde Thomas M, Bar Jair, Barshack Iris, Ben-David Uri, Ishay-Ronen Dana, Maoz Ben M, Satchi-Fainaro Ronit
Department of Physiology and Pharmacology, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, Israel.
Brain. 2025 May 13;148(5):1740-1756. doi: 10.1093/brain/awae347.
Over the last two decades, the diagnosis and treatment of breast cancer patients have improved considerably. However, brain metastases remain a major clinical challenge and a leading cause of mortality. Thus, a better understanding of the pathways involved in the metastatic cascade is essential. To this end, we have investigated the reciprocal effects of astrocytes and breast cancer cells, employing traditional 2D cell culture and our unique 3D multicellular tumouroid models. Our findings revealed that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in breast cancer outgrowth to the brain. Elucidating the key players in astrocyte-breast cancer cells crosstalk, we found that CCL2 is highly expressed in breast cancer brain metastases tissue sections from both patients and mice. Our in vitro and in vivo models further confirmed that CCL2 has a functional role in brain metastasis. Given their aggressive nature, we sought additional immune checkpoints for rationale combination therapy. Among the promising candidates were the adhesion molecule P-selectin, which we have recently shown to play a key role in the crosstalk with microglia cells and the co-inhibitory receptor PD-1, the main target of currently approved immunotherapies. Finally, combining CCL2 inhibition with immunomodulators targeting either PD-1/PD-L1 or P-selectin/P-Selectin Ligand-1 axes in our human 3D tumouroid models and in vivo presented more favourable outcomes than each monotherapy. Taken together, we propose that CCL2-CCR2/CCR4 is a key pathway promoting breast cancer brain metastases and a promising target for an immunotherapeutic combination approach.
在过去的二十年里，乳腺癌患者的诊断和治疗有了显著改善。然而，脑转移仍然是一个主要的临床挑战和死亡的主要原因。因此，更好地了解转移级联所涉及的途径至关重要。为此，我们采用传统的二维细胞培养和独特的三维多细胞肿瘤类器官模型，研究了星形胶质细胞和乳腺癌细胞的相互作用。我们的研究结果表明，星形胶质细胞增强了乳腺癌细胞的增殖、迁移和侵袭，表明星形胶质细胞在乳腺癌向脑转移的过程中起支持作用。在阐明星形胶质细胞与乳腺癌细胞相互作用的关键因素时，我们发现CCL2在患者和小鼠的乳腺癌脑转移组织切片中高表达。我们的体外和体内模型进一步证实CCL2在脑转移中具有功能性作用。鉴于它们的侵袭性，我们寻找其他免疫检查点进行合理的联合治疗。有前景的候选者包括黏附分子P-选择素，我们最近发现它在与小胶质细胞的相互作用中起关键作用，以及共抑制受体PD-1，它是目前批准的免疫疗法的主要靶点。最后，在我们的人类三维肿瘤类器官模型和体内，将CCL2抑制与靶向PD-1/PD-L1或P-选择素/P-选择素配体-1轴的免疫调节剂联合使用，比单一疗法产生了更有利的结果。综上所述，我们认为CCL2-CCR2/CCR4是促进乳腺癌脑转移的关键途径，也是免疫治疗联合方法的一个有前景的靶点。
