肿瘤相关星形胶质细胞通过分泌脂联素-2促进Sonic Hedgehog型髓母细胞瘤的肿瘤进展。
Tumor-associated astrocytes promote tumor progression of Sonic Hedgehog medulloblastoma by secreting lipocalin-2.
发表日期：2023 Sep 18
作者：
Haishuang Li, Yuqing Liu, Yantao Liu, Luzheng Xu, Ziwen Sun, Danfeng Zheng, Xiaodan Liu, Chen Song, Yu Zhang, Hui Liang, Bao Yang, Xinxia Tian, Jianyuan Luo, Qing Chang
来源：
Brain Structure & Function
摘要：
皮状小体信号（Sonic Hedgehog，SHH）亚型髓母细胞瘤（medulloblastoma，MB）占据了所有MB亚型的约25%。肿瘤微环境（tumor microenvironment，TME）可能在肿瘤进展和治疗抗性中发挥关键作用。肿瘤相关星形胶质细胞（tumor-associated astrocytes，TAAs）通过多重旁分泌信号重塑，推动肿瘤进展。然而，TAAs如何调节MB细胞的机制尚不明确。在这里，我们阐明了TAAs在SHH-MB发展过程中呈现出特定而动态的模式。在肿瘤进展期间，大部分TAAs聚集于肿瘤边缘，而不是在早期肿瘤中均匀分布。我们进一步证明，由TAAs分泌的脂联素2（lipocalin-2，LCN2）可以促进肿瘤生长，并且与MB患者的恶劣预后相关。在体外通过抑制TAAs中的LCN2，可以阻止MB细胞的增殖和迁移能力。此外，我们确定了TAAs通过STAT3信号通路分泌LCN2来加速肿瘤生长。因此，在体内外分别通过STAT3信号通路抑制剂WP1066和AAV-Lcn2 shRNA，可以消除LCN2对肿瘤进展的影响。总之，我们首次阐明了由TAAs分泌的LCN2可以通过STAT3信号通路促进MB肿瘤进展，并具有潜在的预后价值。我们的研究揭示了重新规划SHH-MB的TME的新视角，并为针对TAAs的潜在治疗策略提供了依据。© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.
Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. Here, we illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors. We further demonstrated that lipocalin-2 (LCN2) secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV-Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.