Punovuori Karolina, Bertillot Fabien, Miroshnikova Yekaterina A, Binner Mirjam I, Myllymäki Satu-Marja, Follain Gautier, Kruse Kai, Routila Johannes, Huusko Teemu, Pellinen Teijo, Hagström Jaana, Kedei Noemi, Ventelä Sami, Mäkitie Antti, Ivaska Johanna, Wickström Sara A
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland.
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland; Department of Cell and Tissue Dynamics, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
Cell. 2024 Dec 12;187(25):7267-7284.e20. doi: 10.1016/j.cell.2024.09.046. Epub 2024 Oct 28.
Epithelial tumors are characterized by abundant inter- and intra-tumor heterogeneity, which complicates diagnostics and treatment. The contribution of cancer-stroma interactions to this heterogeneity is poorly understood. Here, we report a paradigm to quantify phenotypic diversity in head and neck squamous cell carcinoma (HNSCC) with single-cell resolution. By combining cell-state markers with morphological features, we identify phenotypic signatures that correlate with clinical features, including metastasis and recurrence. Integration of tumor and stromal signatures reveals that partial epithelial-mesenchymal transition (pEMT) renders disease outcome highly sensitive to stromal composition, generating a strong prognostic and predictive signature. Spatial transcriptomics and subsequent analyses of cancer spheroid dynamics identify the cancer-associated fibroblast-pEMT axis as a nexus for intercompartmental signaling that reprograms pEMT cells into an invasive phenotype. Taken together, we establish a paradigm to identify clinically relevant tumor phenotypes and discover a cell-state-dependent interplay between stromal and epithelial compartments that drives cancer aggression.
上皮肿瘤的特征是肿瘤间和肿瘤内存在大量异质性，这使得诊断和治疗变得复杂。目前人们对癌-基质相互作用对这种异质性的作用了解甚少。在此，我们报告了一种以单细胞分辨率量化头颈部鳞状细胞癌（HNSCC）表型多样性的范例。通过将细胞状态标记与形态学特征相结合，我们确定了与包括转移和复发在内的临床特征相关的表型特征。肿瘤和基质特征的整合显示，部分上皮-间质转化（pEMT）使疾病结局对基质组成高度敏感，从而产生强大的预后和预测特征。空间转录组学以及随后对癌症球体动态的分析确定了癌症相关成纤维细胞-pEMT轴是隔室间信号传导的枢纽，该信号传导将pEMT细胞重编程为侵袭性表型。综上所述，我们建立了一种识别临床相关肿瘤表型的范例，并发现了基质和上皮隔室之间依赖细胞状态的相互作用，这种相互作用驱动癌症侵袭。
