PO.TB05.01 · 肿瘤生物学

SMARCD3调控的浦肯野细胞迁移是小脑发育和3组髓母细胞瘤转移的基础

SMARCD3-regulated Purkinje cell migration underlies cerebellar development and group 3 medulloblastoma metastasis

编号 629 展板 8 时间 4/19 02:00–05:00 区域 Section 26 主讲 Yash Patel, BS

分会场 Developmental Origins, Drivers, and Heterogeneity in Pediatric Cancer

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作者与单位 Authors & Affiliations

Yash Patel¹, Han Zou¹, Allen Zheng², Anjali Talluru², Nirja Divekar², Chaim Sneiderman¹, Meghana Dodda², Katie Dietrich², Siheng Chao², Sameer Agnihotri³, Gary Kohanbash³, Antony Michealraj³, Ian Pollack³, Baoli Hu³

¹University of Pittsburgh School of Medicine, Pittsburgh, PA,²University of Pittsburgh, Pittsburgh, PA,³Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA

摘要 Abstract

中文摘要

髓母细胞瘤（MB）是一种起源于小脑的异质性脑肿瘤，是最常见的儿童恶性脑肿瘤。3组是四种分子亚组（WNT、SHH、3组和4组）之一，是儿童中最具侵袭性和恶性的类型，通常在诊断时即伴有转移。在本研究中，我们发现SWI/SNF染色质重塑复合体的核心组分SMARCD3/BAF60c（下文简称SMARCD3）在3组MB和发育中小脑的浦肯野细胞（PCs）中高表达。SMARCD3表达升高与较差的患者预后、MB转移以及Disabled1（DAB1）-Reelin信号通路的激活相关，而该通路是小脑发育过程中PC迁移和定位所必需的。在早期PC中条件性敲除SMARCD3会导致小鼠胚胎期和出生后早期死亡，存活动物则表现出明显的运动协调和平衡缺陷。对SMARCD3敲除的小鼠小脑组织进行免疫染色显示PC排列紊乱和树突分支减少，证实了SMARCD3-Reelin通路功能在PC迁移、定位和成熟中的关键作用。这些数据表明，SMARCD3相关的SWI/SNF染色质重塑复合体在小脑发育过程中调控Reelin信号通路以实现PC迁移和定位；然而，这一神经发育程序被劫持以促进MB的转移播散。为进一步理解该机制，我们分析了人和小鼠小脑的时空基因表达和染色质可及性数据，注意到SMARCD3/Reelin信号在成熟小脑中降低，但在转移性髓母细胞瘤中高度上调。该研究提供了令人信服的功能证据，证明SMARCD3及相关SWI/SNF复合体参与小脑发育、肿瘤转移，以及早期脑发育与肿瘤发生之间的分子联系，为开发针对MB患者的创新疗法提供了新的理论依据。

查看英文原文 English abstract

Medulloblastoma (MB) is a heterogeneous brain tumor arising in the cerebellum and is the most common malignant pediatric brain tumor. Group 3, one of four molecular MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children, usually characterized by metastasis at diagnosis. In this study, we identify that SMARCD3/BAF60c (SMARCD3 hereafter), a core component of the SWI/SNF chromatin-remodeling complexes, is highly expressed in Group 3 MB and Purkinje cells (PCs) of the developing cerebellum. Elevated SMARCD3 expression is associated with poorer patient outcomes, MB metastasis, and activation of the Disabled1 (DAB1)-Reelin signaling pathway that is required for PC migration and positioning during cerebellar development. Conditional SMARCD3 deletion in early PCs results in embryonic and early postnatal lethality in mice, and the surviving animals exhibit significant deficits in motor coordination and balance. Immunostaining of SMARCD3 deleted murine cerebellar tissue shows disorganized PC alignment and reduced dendritic branching, confirming the critical role of the SMARCD3-Reelin pathway function in PC migration, positioning, and maturation. These data demonstrate that the SMARCD3-associated SWI/SNF chromatin-remodeling complex regulates Reelin signaling pathway in PC migration and positioning during cerebellar development; however, this neurodevelopmental program is hijacked to promote MB metastatic dissemination. To further understand this mechanism, we analyzed spatiotemporal gene expression and chromatin accessibility data of the human and mouse cerebellum, noting the SMARCD3/Reelin signaling decreased in the mature cerebellum, but is highly upregulated in metastatic medulloblastoma. The study provides compelling functional evidence of SMARCD3 and the associated SWI/SNF complexes' involvement in cerebellar development, tumor metastasis, and the molecular connections between early brain development and tumorigenesis, offering new rationales for the development of innovative therapies for patients with MB.

利益披露 Disclosure

Y. Patel, None.. H. Zou, None.. A. Zheng, None.. A. Talluru, None.. N. Divekar, None.. C. Sneiderman, None.. M. Dodda, None.. K. Dietrich, None.. S. Chao, None.. S. Agnihotri, None.. G. Kohanbash, None.. A. Michealraj, None.. I. Pollack, None.. B. Hu, None.

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