YAP-Driven Oral Epithelial Stem Cell Malignant Reprogramming at Single Cell Resolution.

Farhoud Faraji, Sydney I Ramirez, Lauren Clubb, Kuniaki Sato, Valeria Burghi, Thomas S Hoang, Adam Officer, Paola Y Anguiano Quiroz, William Mg Galloway, Zbigniew Mikulski, Kate Medetgul-Ernar, Pauline Marangoni, Kyle B Jones, Alfredo A Molinolo, Kenneth Kim, Kanako Sakaguchi, Joseph A Califano, Quinton Smith, Alon Goren, Ophir D Klein, Pablo Tamayo, J Silvio Gutkind
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Abstract

Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processes underlying oral epithelial progenitor cell reprogramming into tumor initiating cells (TIC) at single cell resolution. TIC displayed a distinct stem-like state, defined by aberrant proliferative, hypoxic, squamous differentiation, and partial epithelial to mesenchymal (pEMT) invasive gene programs. YAP-mediated TIC programs included the activation of oncogenic transcriptional networks and mTOR signaling, and the recruitment of myeloid cells to the invasive front contributing to tumor infiltration. TIC transcriptional programs are conserved in human head and neck cancer and associated with poor patient survival. These findings illuminate processes underlying cancer initiation at single cell resolution, and identify candidate targets for early cancer detection and prevention.

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在体内以单细胞分辨率将口腔上皮祖细胞直接重编程为癌症干细胞。
肿瘤起始是肿瘤发生的第一步,在这一过程中,正常祖细胞经历了细胞命运转变为癌细胞的过程。大多数调查实体瘤致癌机制的研究都依赖于对已形成的恶性病变的分析,因此无法直接捕捉正常祖细胞重编程为癌细胞的过程。在这里,我们在基因工程系统中使用时空控制的癌基因表达,证明同时激活YAP和HPV E6-E7介导的抑制肿瘤途径足以将口腔上皮祖细胞(OEPCs)快速重编程为癌症干细胞(CSCs)。对这些新生 CSC 的单细胞分析揭示了驱动肿瘤发生的标志性转录程序。重要的是,这些富含癌干细胞的表达特征将正常组织与恶性头颈部肿瘤区分开来,并与患者存活率低有关。阐明OEPC到CSC重编程的内在机制可能会为阻止恶性前细胞转化为浸润性癌提供新的见解:YAP和HPV E6-E7将口腔上皮祖细胞重编程为癌症干细胞。摘要:YAP和HPV E6-E7将口腔上皮祖细胞重编程为癌症干细胞。单细胞分析揭示了肿瘤启动的转录结构。CSC转录程序将正常组织与癌细胞区分开来:
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