肿瘤微环境的空间组织对生物学和治疗反应产生重大影响。在这里，我们对HPV阴性口腔鳞状细胞癌（OSCC）进行综合单细胞和空间转录组分析，以全面表征肿瘤核心（TC）和前沿（LE）转录结构中的恶性细胞。我们展示了TC和LE具有独特的转录谱、邻近细胞组成和配体-受体相互作用。我们证明了与LE相关的基因表达谱在不同癌症中是保守的，而TC则是组织特异性的，突出了肿瘤进展和侵袭的共同机制。此外，我们发现LE基因签名与临床预后不良有关，而TC基因签名与多种癌症类型的良好预后有关。最后，我们使用一个基于计算模拟的方法描述了与药物反应可预测相关的OSCC细胞发育的空间调控模式。我们的工作为TC和LE生物学以及交互式空间地图（http://www.pboselab.ca/spatial_OSCC/; http://www.pboselab.ca/dynamo_OSCC/）提供了全癌症的洞察，这对于开发新型靶向治疗具有重要意义。© 2023. Springer Nature Limited.

The spatial organization of the tumor microenvironment has a profound impact on biology and therapy response. Here, we perform an integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize malignant cells in tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, neighboring cellular compositions, and ligand-receptor interactions. We demonstrate that the gene expression profile associated with the LE is conserved across different cancers while the TC is tissue specific, highlighting common mechanisms underlying tumor progression and invasion. Additionally, we find our LE gene signature is associated with worse clinical outcomes while TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biology and interactive spatial atlases ( http://www.pboselab.ca/spatial_OSCC/ ; http://www.pboselab.ca/dynamo_OSCC/ ) that can be foundational for developing novel targeted therapies.© 2023. Springer Nature Limited.