PO.TB10.02 · 肿瘤生物学

单细胞与空间多组学揭示ccRCC肺转移灶中存在癌相关成纤维细胞淋巴细胞排斥位点，形成受限的TME

ccRCC lung metastases harbor cancer associated fibroblast lymphocyte exclusion sites that form a confined TME as revealed by single cell and spatial multi-omics

编号 6113 展板 4 时间 4/21 02:00–05:00 区域 Section 28 主讲 Yufei Wang, PhD

分会场 Metastasis and Organ-Specific Microenvironmental Evolution

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作者与单位 Authors & Affiliations

Yufei Wang¹, Jae-Won Cho², Yasmin Nabil Laimon², Wenxin Xu¹, Kun Huang¹, Aseman Bagheri Sheshdeh², Nithyassree Murugan¹, Hsien-Chi Yuan¹, Jon Wee², David Alexander Braun³, Toni K. Choueiri¹, Catherine J. Wu¹, Sabina Signoretti², Gordon J. Freeman¹, Martin Hemberg², Wayne A. Marasco⁴

¹Dana-Farber Cancer Institute, Boston, MA,²Brigham and Women's Hospital, Boston, MA,³Yale School of Medicine, New Haven, CT,⁴Associate Professor, Dana-Farber Cancer Institute, Boston, MA

摘要 Abstract

中文摘要

肿瘤进展与转移由癌细胞及其周围肿瘤微环境（TME）之间的相互作用所驱动。研究原发肿瘤与转移肿瘤的时空转录组和蛋白质组特征，有助于阐明空间结构的差异如何塑造TME并促进肿瘤转移。在此，我们使用三种不同的空间转录组和蛋白质组平台——CosMx、Xenium和CODEX，对六例原发性透明细胞肾细胞癌（ccRCC）标本及其肺转移灶进行了分析。在完成细胞分割与注释后，我们整合了细胞背景与空间信息，通过识别具有相似细胞类型组成的空间区域来鉴定生态位（niche）。这揭示了12个特征性生态位，包括癌、基质、肺泡和三级淋巴结构（TLS）生态位，由25种不同的细胞类型构成。此外，我们分析了细胞间通讯与结构，以理解原发性与转移性ccRCC中的细胞间相互作用及空间组织。结构分析显示，转移病灶具有与原发肿瘤不同的结构，我们称之为癌相关成纤维细胞淋巴细胞排斥位点（Cancer Associated fibroblaST Lymphocyte Exclusion Sites，CASTLES）。CASTLES的关键特征是恶性细胞被癌相关成纤维细胞（CAFs）、内皮细胞以及肿瘤相关巨噬细胞（TAMs）所包围，构成一道物理屏障。相比之下，原发性ccRCC细胞则可被肿瘤浸润白细胞（TILs）接触。这种空间组织的差异支持了转移性癌细胞的侵袭性特征。我们的结果显示了空间结构对原发性与转移性ccRCC的影响，以及细胞背景的空间组织与细胞间通讯之间的关系。此外，研究提示癌相关成纤维细胞（CAFs）与免疫细胞是ccRCC TME的重要组成部分。它们之间的相互作用不仅是肿瘤进展的主要因素，也是限制转移性ccRCC治疗反应的主要因素。

查看英文原文 English abstract

Tumor progression and metastasis is driven by interplays between cancer cells and their surrounding tumor microenvironment (TME). Investigating the spatiotemporal transcriptomic and proteomic profile of primary and metastatic tumors sheds light on how differences in spatial architecture shape the TME and promote tumor metastasis. Here, we profiled six primary clear cell renal cell carcinoma (ccRCC) specimens and their lung metastases using three different spatial transcriptomic and proteomic platforms: CosMx, Xenium and CODEX. After cell segmentation and annotation, we incorporated the cellular context and spatial information to identify niches by identifying spatial regions with similar cell type composition. This revealed 12 distinctive niches including cancer, stroma, alveolar, and tertiary lymphoid structure (TLS) niches, formed by 25 different cell types. Furthermore, we analyzed cell-cell communication and architecture were analyzed to understand the intercellular interplay and spatial organization in primary and metastatic ccRCC. The architecture analysis showed that the metastatic lesion has a distinct architecture compared to the primary tumor which we refer to as Cancer Associated fibroblaST Lymphocyte Exclusion Sites (CASTLES). The key characteristic of CASTLES is that malignant cells surrounded by cancer associated fibroblasts (CAFs), endothelial cells as well as tumor associated macrophages (TAMs), constituting a physical barrier. In contrast, primary ccRCC cells were accessible to tumor infiltrating leukocytes (TILs). This difference in spatial organization supports the aggressive characteristics of metastatic cancer cells. Our results show the impact of spatial architecture on primary and metastatic ccRCC, as well as the relation between spatial organization of the cellular context and cell-cell communication. In addition, it suggests that cancer-associated fibroblasts (CAFs) and immune cells are essential components of the ccRCC TME. Their interaction constitutes a major factor not only for tumor progression but also limiting therapy response in metastatic ccRCC.

利益披露 Disclosure

Y. Wang, None.. J. Cho, None.. Y. Nabil Laimon, None.. W. Xu, None.. K. Huang, None.. A. Bagheri Sheshdeh, None.. N. Murugan, None.. H. Yuan, None.. J. Wee, None.

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