Cui Kangli, Chen Wenwen, Cao Rongkai, Xie Yingying, Wang Peng, Wu Yunsong, Wang Yaqing, Qin Jianhua
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
University of Chinese Academy of Sciences, Beijing, China.
Cell Regen. 2022 Mar 7;11(1):7. doi: 10.1186/s13619-021-00102-7.
Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero, maternal health characteristics such as psychiatric disorders, and cancer. Breast cancer is one of the most common cancers worldwide arising pregnancy. However, it is not clear whether the breast cancer might influence the brain development of fetus. Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs. In this work, we engineered human induced pluripotent stem cells (hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell (MCF-7) derived-exosomes on the early neurodevelopment of brain. The formed brain organoids can recapitulate essential features of embryonic human brain at early stages, in terms of neurogenesis, forebrain regionalization, and cortical organization. Treatment with breast cancer cell derived-exosomes, brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6. RNA-seq analysis reflected several activated signaling pathways associated with breast cancer, medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes. These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids. It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.
早期人类大脑发育可能受到多种产前因素的影响，这些因素包括子宫内的化学物质暴露、母亲的健康特征（如精神疾病）以及癌症。乳腺癌是全球范围内孕期最常见的癌症之一。然而，目前尚不清楚乳腺癌是否会影响胎儿的大脑发育。乳腺癌细胞分泌的外泌体在介导不同器官之间的细胞间通讯和相互作用中起着关键作用。在这项研究中，我们在一系列微柱芯片中构建了源自人诱导多能干细胞（hiPSC）的脑类器官，并探究了乳腺癌细胞（MCF-7）来源的外泌体对大脑早期神经发育的影响。所形成的脑类器官在神经发生、前脑区域化和皮质组织方面可以重现早期胚胎人类大脑的基本特征。用乳腺癌细胞来源的外泌体处理后，脑类器官中干性相关标志物OCT4和前脑标志物PAX6的表达增强。RNA测序分析反映了肿瘤来源的外泌体诱导的脑类器官中与乳腺癌、髓母细胞瘤和神经发生相关的几种激活信号通路。这些结果表明，乳腺癌细胞来源的外泌体可能导致脑类器官中神经发育受损和脑类器官的癌变。这可能意味着患有乳腺癌的孕妇的胎儿出生后有神经发育障碍受损的风险。
