Spatial Transcriptomic Landscape of Canine Oral Squamous Cell Carcinoma.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stephanie Goldschmidt, Clifford G Tepper, Jack Goon, Maria Soltero-Rivera, Robert Rebhun, Andrew C Birkeland, Xiao-Jing Wang, Ryan R Davis, Stephenie Y Liu, Iris Rivas, Brian Murphy, Natalis Vapniarsky
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Abstract

Canine oral squamous cell carcinoma (COSCC) is the second most common oral tumor in dogs and the most relevant for comparative human trials as a spontaneous large animal model of disease. Historical genomic work has focused primarily on bulk sequencing. The present study describes the complete transcriptomic landscape of COSCC with spatial distinction between the surface tumor, deep invasive tumor, peritumoral dysplastic epithelium, and tumor microenvironment compared to matched normal oral samples. Each region demonstrated distinct molecular signatures. Genes related to epithelial growth factor (EGFR) and epithelial-mesenchymal transformation (EMT) were upregulated in both peritumoral dysplasia and surface cancer. Additionally, the KRAS gene set, KRT17, and SSP1 were enriched in cancer. We identified five genes that represent dysplastic lesion with high potential for malignant transformation (FZD4, GAS1, HACD2, NOG, and SLC39A6). Also, three genes, SFRP4, FZD1, and IL34 represented a specific signature of the invasive portion of the COSCC that should be explored for prognostic value as a biomarker of malignancy. Lastly, we verified the immunomodulatory tumor microenvironment detecting an increase in macrophages and an abundance of IL-10 secretion. The other predominant leukocytes were T-cells, with CD4+ T-cells being the most prevalent. CD4+ T cells expressed transcripts for both stimulatory (Inducible T-cell Co-Stimulator (ICOS) and inhibitory molecules (CTLA4). The observed high CTLA4 suggests that this inhibitory signal may be preventing a robust antitumor immune response. Taken together, this study identified multiple targets to be explored for biomarkers of malignancy, prediction of tumor behavior, and potential targets for development of novel therapies.

犬口腔鳞状细胞癌的空间转录组学研究。
犬口腔鳞状细胞癌(COSCC)是犬中第二大常见的口腔肿瘤,作为一种自发的大型动物疾病模型,与人类比较试验最相关。历史上的基因组工作主要集中在批量测序上。本研究描述了COSCC的完整转录组景观,与匹配的正常口腔样本相比,在肿瘤表面、深部浸润性肿瘤、瘤周发育不良上皮和肿瘤微环境之间存在空间差异。每个区域都显示出不同的分子特征。与上皮生长因子(EGFR)和上皮-间充质转化(EMT)相关的基因在肿瘤周围发育不良和表面癌中均上调。此外,KRAS基因集、KRT17和SSP1在癌症中富集。我们确定了5个具有高恶性转化潜力的发育不良病变基因(FZD4、GAS1、HACD2、NOG和SLC39A6)。此外,三个基因,SFRP4, FZD1和IL34代表了COSCC侵袭部分的特定特征,作为恶性肿瘤的生物标志物,应该探索其预后价值。最后,我们验证了免疫调节肿瘤微环境检测到巨噬细胞的增加和IL-10的丰富分泌。其他主要的白细胞是t细胞,CD4+ t细胞是最普遍的。CD4+ T细胞表达刺激(诱导性T细胞共刺激物(ICOS))和抑制分子(CTLA4)的转录本。观察到的高CTLA4表明这种抑制信号可能阻止了强大的抗肿瘤免疫反应。综上所述,本研究确定了多个靶点,以探索恶性肿瘤的生物标志物,预测肿瘤行为,以及开发新疗法的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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