Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities.
Molecular homology between canine spontaneous oral squamous cell carcinomas and human head-and-neck squamous cell carcinomas reveals disease drivers and therapeutic vulnerabilities.
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DOI：
10.1016/j.neo.2020.10.003
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Markkanen E
中科院分区：
文献类型：
--
作者：
Guscetti F;Nassiri S;Beebe E;Rito Brandao I;Graf R;Markkanen E
激光捕获显微解剖（LCM）和RNAseq揭示了COSCC和与HNSCC的分子同源性的详细见解。CDK4/6作为COSCC治疗易感性的鉴定这强调了自发性COSCC作为HNSCC模型的潜力，该模型可以探究治疗脆弱性，并支持新疗法从实验室到床边的转化。自发发生的犬口腔鳞状细胞癌（COSCC）被认为是人类头颈部鳞状细胞癌（HNSCC）的有用模型。然而，迄今为止，对COSCC的分子基础仍然知之甚少。为了确定COSCC中与癌细胞相关的变化，我们使用激光捕获显微解剖结合rna测序（RNAseq）技术，对临床福尔马林固定石蜡包埋标本中的肿瘤细胞和匹配的正常上皮进行了特异性分析。我们的研究结果确定了上皮-间质转化（EMT）、经典肿瘤促进（如E2F、KRAS、MYC、mTORC1和TGFB1信号）和免疫相关通路在COSCC肿瘤上皮中的重要作用。对COSCC与43对来自癌症基因组图谱的肿瘤/正常HNSCC的比较分析显示，在转录重编程方面具有高度的同源性，并确定了与细胞周期进展、免疫过程和细胞分化丧失相关的过程可能是该疾病的主要驱动因素。与HNSCC类似，我们的分析表明，在COSCC中存在zeb2驱动的部分EMT，并且在COSCC中发现了KRT14和KRT17的选择性上调。除了转录特征的同源性外，我们还发现物种之间的治疗脆弱性高度保守：包括PD-L1和CTLA-4的表达增加，与EMT一致，揭示了免疫检查点疗法的潜力，以及CDK4/6的过表达使COSCC对palbociclib治疗敏感。总之，我们的数据显著扩展了目前对COSCC分子异常的认识，并强调了自发性COSCC作为HNSCC模型的潜力，以询问治疗脆弱性并支持新疗法从实验室到床边的转化。
Laser-capture microdissection (LCM) followed by RNAseq reveals detailed insights into COSCC and molecular homologies to HNSCC. Identification of CDK4/6 as therapeutic vulnerability in COSCC. This underlines the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside. Spontaneously occurring canine oral squamous cell carcinomas (COSCC) are viewed as a useful model for human head and neck squamous cell carcinomas (HNSCC). To date however, the molecular basis of COSCC remains poorly understood. To identify changes pertinent to cancer cells in COSCC, we specifically analyzed tumor cells and matched normal epithelium from clinical formalin-fixed paraffin-embedded specimens using laser-capture-microdissection coupled with RNA-sequencing (RNAseq). Our results identify strong contributions of epithelial-to-mesenchymal transition (EMT), classical tumor-promoting (such as E2F, KRAS, MYC, mTORC1, and TGFB1 signaling) and immune-related pathways in the tumor epithelium of COSCC. Comparative analyses of COSCC with 43 paired tumor/normal HNSCC from The Cancer Genome Atlas revealed a high homology in transcriptional reprogramming, and identified processes associated with cell cycle progression, immune processes, and loss of cellular differentiation as likely central drivers of the disease. Similar to HNSCC, our analyses suggested a ZEB2-driven partial EMT in COSCC and identified selective upregulation of KRT14 and KRT17 in COSCC. Beyond homology in transcriptional signatures, we also found therapeutic vulnerabilities strongly conserved between the species: these included increased expression of PD-L1 and CTLA-4, coinciding with EMT and revealing the potential for immune checkpoint therapies, and overexpression of CDK4/6 that sensitized COSCC to treatment with palbociclib. In summary, our data significantly extend the current knowledge of molecular aberrations in COSCC and underline the potential of spontaneous COSCC as a model for HNSCC to interrogate therapeutic vulnerabilities and support translation of novel therapies from bench to bedside.
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