Feng Chao, Wang Yaobang, Song Wuyue, Liu Tao, Mo Han, Liu Hui, Wu Shulin, Qin Zezu, Wang Zhenxing, Tao Yuting, He Liangyu, Tang Shaomei, Xie Yuanliang, Wang Qiuyan, Li Tianyu
Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, China.
Front Immunol. 2024 Dec 20;15:1522582. doi: 10.3389/fimmu.2024.1522582. eCollection 2024.
Muscle-invasive bladder cancer (MIBC) is a prevalent cancer characterized by molecular and clinical heterogeneity. Assessing the spatial heterogeneity of the MIBC microenvironment is crucial to understand its clinical significance.
In this study, we used imaging mass cytometry (IMC) to assess the spatial heterogeneity of MIBC microenvironment across 185 regions of interest in 40 tissue samples. We focused on three primary parameters: tumor (T), leading-edge (L), and nontumor (N). Cell gating was performed using the Cytobank platform. We calculated the Euclidean distances between cells to determine cellular interactions and performed single-cell RNA sequencing (scRNA-seq) to explore the molecular characteristics and mechanisms underlying specific fibroblast (FB) clusters. scRNA-seq combined with spatial transcriptomics (ST) facilitated the identification of ligand-receptor (L-R) pairs that mediate interactions between specific FB clusters and endothelial cells. Machine learning algorithms were used to construct a prognostic gene signature.
The microenvironments in the N, L, and T regions of MIBC exhibited spatial heterogeneity and regional diversity in their components. A distinct FB cluster located in the L region-identified as S3-is strongly associated with poor prognosis. IMC analyses demonstrated a close spatial association between S3 and endothelial cells, with S3-positive tumors exhibiting increased blood vessel density and altered vascular morphology. The expression of vascular endothelial growth factor receptor and active vascular sprouting were significant in S3-positive tumors. scRNA-seq and ST analyses indicated that the genes upregulated in S3 were associated with angiogenesis. NOTCH1-JAG2 signaling pathway was identified as a significant L-R pair specific to S3 and endothelial cell interactions. Further analysis indicated that YAP1 was a potential regulator of S3. Machine learning algorithms and Gene Set Variation Analysis were used to establish an S3-related gene signature that was associated with the poor prognosis of tumors including MIBC, mesothelioma, glioblastoma multiforme, lower-grade glioma, stomach adenocarcinoma, uveal melanoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, and lung squamous cell carcinoma.
We assessed the spatial landscape of the MIBC microenvironment and revealed a specific FB cluster with prognostic potential. These findings offer novel insights into the spatial heterogeneity of the MIBC microenvironment and highlight its clinical significance.
肌层浸润性膀胱癌（MIBC）是一种常见的癌症，具有分子和临床异质性。评估MIBC微环境的空间异质性对于理解其临床意义至关重要。
在本研究中，我们使用成像质谱流式细胞术（IMC）评估了40个组织样本中185个感兴趣区域的MIBC微环境的空间异质性。我们关注三个主要参数：肿瘤（T）、前沿（L）和非肿瘤（N）。使用Cytobank平台进行细胞门控。我们计算细胞之间的欧几里得距离以确定细胞间相互作用，并进行单细胞RNA测序（scRNA-seq）以探索特定成纤维细胞（FB）簇的分子特征和潜在机制。scRNA-seq与空间转录组学（ST）相结合，有助于识别介导特定FB簇与内皮细胞之间相互作用的配体-受体（L-R）对。使用机器学习算法构建预后基因特征。
MIBC的N、L和T区域的微环境在其组成成分上表现出空间异质性和区域多样性。位于L区域的一个独特的FB簇（被鉴定为S3）与预后不良密切相关。IMC分析表明S3与内皮细胞之间存在紧密的空间关联，S3阳性肿瘤的血管密度增加且血管形态改变。血管内皮生长因子受体的表达和活跃的血管生成在S3阳性肿瘤中显著。scRNA-seq和ST分析表明，S3中上调的基因与血管生成相关。NOTCH1-JAG2信号通路被确定为S3与内皮细胞相互作用特有的重要L-R对。进一步分析表明YAP1是S3的潜在调节因子。使用机器学习算法和基因集变异分析建立了一个与S3相关的基因特征，该特征与包括MIBC、间皮瘤、多形性胶质母细胞瘤、低级别胶质瘤、胃腺癌、葡萄膜黑色素瘤、肾透明细胞癌、肾乳头状细胞癌和肺鳞状细胞癌等肿瘤的预后不良相关。
我们评估了MIBC微环境的空间格局，并揭示了一个具有预后潜力的特定FB簇。这些发现为MIBC微环境的空间异质性提供了新的见解，并突出了其临床意义。
