PO.TB10.07 · 肿瘤生物学
使用全转录组空间分子成像面板对转移性结直肠癌小鼠模型进行亚细胞成像
Subcellular imaging of murine models of metastatic colorectal cancer using a whole transcriptome spatial molecular imaging panel
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摘要 Abstract
中文摘要
空间转录组学能够对复杂组织内的分子和细胞异质性进行原位表征。然而,此类高通量亚细胞分辨率分析此前尚无法应用于小鼠模型,而后者在癌症生物学和治疗开发中处于核心地位。为弥补这一空白,我们开发了一种新的小鼠全转录组(WTX)检测,包含超过20,000个靶标,能够实现全面的亚细胞成像,并具有未来多组学整合的潜力。使用CosMx空间分子成像仪(SMI),我们对来自Kras突变结直肠癌晚期小鼠模型的福尔马林固定石蜡包埋(FFPE)原发性和转移性结直肠癌进行了分析。每张玻片均按照标准CosMx流程处理。进行UMAP和聚类分析以识别空间分辨的细胞群。细胞类型注释以经典标志基因为指导。在原发性结肠癌和肝转移灶中,均探究了肿瘤上皮及其支持性微环境对靶向KRAS抑制反应的转录异质性和适应性可塑性。CosMx小鼠WTX检测在肝癌和结肠癌样本中均表现出稳健的检测灵敏度和动态范围。在肿瘤和基质区室内识别出不同的细胞龛,揭示了对应于肝细胞、免疫细胞和成纤维细胞亚型的转录学独特簇。在结肠肿瘤中,空间上不同的肿瘤区域表现出差异性的基因表达模式,提示存在不同的微环境影响。在原发和继发疾病的各肿瘤区室中均观察到对治疗挑战的转录适应,凸显了可用于驱动改善治疗反应的新颖、可利用途径。我们首次在CosMx平台上应用小鼠全转录组检测,实现了跨越>20,000个靶标的亚细胞空间分辨率。这一新能力为多组学整合开辟了途径,可全面研究小鼠模型中的肿瘤-基质相互作用和免疫微环境。总之,这些进展架起了临床前与转化空间生物学之间的桥梁,为癌症研究中空间分辨的发现提供了新基础。
查看英文原文 English abstract
Spatial transcriptomics enables in situ characterization of molecular and cellular heterogeneity within complex tissues. However, such high-plex subcellular resolution analysis has not previously been available for mouse models, which are central to cancer biology and therapeutic development. To address this gap, we have developed a new mouse Whole Transcriptome (WTX) assay containing over 20,000 targets, enabling comprehensive subcellular imaging with potential for future multiomic integration. Using the CosMx Spatial Molecular Imager (SMI), we profiled formalin-fixed paraffin-embedded (FFPE) primary and metastatic colorectal cancers from advanced murine models of Kras-mutant colorectal cancer. Each slide was processed according to standard CosMx workflow. UMAP and clustering analyses were performed to identify spatially resolved cell populations. Cell type annotation was guided by canonical marker genes. Transcriptional heterogeneity and adaptive plasticity of the tumour epithelium and supporting micro-environment in response to targeted KRAS inhibition was interrogated in both primary colonic cancers and in hepatic metastases. The CosMx mouse WTX assay demonstrated robust detection sensitivity and dynamic range across both liver and colon cancer samples. Distinct cellular niches were identified within tumor and stromal compartments, revealing transcriptionally unique clusters corresponding to hepatocytes, immune cells, and fibroblast subtypes. In the colon tumor, spatially distinct tumor regions exhibited divergent gene expression patterns, suggesting differential microenvironmental influences. Transcriptional adaptation to therapeutic challenge was observed across tumour compartments in both primary and secondary disease, highlighted novel, exploitable avenues to drive improved therapeutic response. We present the first application of a mouse Whole Transcriptome assay on the CosMx platform, enabling subcellular spatial resolution across >20,000 targets. This new capability opens avenues for multiomic integration, allowing comprehensive investigation of tumor-stroma interactions and immune microenvironments in mouse models. Together, these advances bridge preclinical and translational spatial biology, providing a new foundation for spatially resolved discovery in cancer research.
利益披露 Disclosure
L. Zhang, None..
I. Lee, None..
S. He, None..
M. Shelton, None..
O. J. Sansom, None..
J. M. Beechem, None.