Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
Department of Pathology, Tianjin Medical University, Tianjin, China.
Front Immunol. 2023 Jan 4;13:1042835. doi: 10.3389/fimmu.2022.1042835. eCollection 2022.
Hypoxia is an important characteristic of solid tumors. However, spatial transcriptomics (ST) of hypoxia-associated heterogeneity is not clear.
This study integrated Spatial Transcriptomics (ST) with immunofluorescence to demonstrate their spatial distribution in human claudin-low breast cancer MDA-MB-231 engraft. ST spots were clustered with differentially expression genes. The data were combined with hypoxia-specific marker and angiogenesis marker-labeled serial sections to indicate the spatial distribution of hypoxia and hypoxia-inducted transcriptional profile. Moreover, marker genes, cluster-specific hypoxia genes, and their co-essential relationship were identified and mapped in every clusters. The clinicopathological association of marker genes of hypoxia-dependent spatial clusters was explored in 1904 breast cancers from METABRIC database.
The tumor from center to periphery were enriched into five hypoxia-dependent subgroups with differentially expressed genes, which were matched to necrosis, necrosis periphery, hypoxic tumor, adaptive survival tumor, and invasive tumor, respectively. Different subgroups demonstrated distinct hypoxia condition and spatial heterogeneity in biological behavior and signaling pathways. Cox regression analysis showed that the invasive tumor (cluster 0) and hypoxic tumor (cluster 6) score could be served as independent prognostic factors in claudin-low patients. KM analysis indicated that high invasive tumor (cluster 0) and hypoxic tumor (cluster 6) score was associated with poor prognoses of claudin-low patients. Further analysis showed that hypoxia-induced immune checkpoints, such as CD276 and NRP1, upregulation in invasive tumor to block infiltration and activation of B cells and CD8+ T cells to change tumor immune microenvironment.
This study reveals hypoxia-dependent spatial heterogeneity in claudin-low breast cancer and highlights its potential value as a predictive biomarker of clinical outcomes and immunotherapy response. The molecules found in this study also provided potential molecular mechanisms and therapeutic targets for subsequent studies.
缺氧是实体瘤的一个重要特征。然而，缺氧相关异质性的空间转录组学（ST）尚不清楚。
本研究将空间转录组学（ST）与免疫荧光相结合，以展示其在人 Claudin-低型乳腺癌 MDA-MB-231 移植中的空间分布。ST 点通过差异表达基因聚类。将数据与缺氧特异性标志物和血管生成标志物标记的连续切片相结合，以指示缺氧和缺氧诱导的转录谱的空间分布。此外，鉴定并映射了每个簇中的标记基因、簇特异性缺氧基因及其共必需关系。在 METABRIC 数据库中的 1904 例乳腺癌中探索了缺氧依赖的空间簇标记基因的临床病理相关性。
从中心到外周的肿瘤富集为五个具有差异表达基因的缺氧依赖性亚组，分别与坏死、坏死周围、缺氧肿瘤、适应性存活肿瘤和侵袭性肿瘤相对应。不同的亚组表现出不同的缺氧条件和生物学行为及信号通路的空间异质性。Cox 回归分析表明，侵袭性肿瘤（簇 0）和缺氧肿瘤（簇 6）评分可作为 Claudin-低型患者的独立预后因素。KM 分析表明，高侵袭性肿瘤（簇 0）和缺氧肿瘤（簇 6）评分与 Claudin-低型患者的不良预后相关。进一步分析表明，缺氧诱导的免疫检查点，如 CD276 和 NRP1，在侵袭性肿瘤中上调，以阻止 B 细胞和 CD8+T 细胞的浸润和激活，从而改变肿瘤免疫微环境。
本研究揭示了 Claudin-低型乳腺癌中缺氧依赖性的空间异质性，并强调了其作为临床结局和免疫治疗反应预测生物标志物的潜在价值。本研究中发现的分子也为后续研究提供了潜在的分子机制和治疗靶点。
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