Gene expression profiles of the original tumors influence the generation of PDX models of lung squamous cell carcinoma
Gene expression profiles of the original tumors influence the generation of PDX models of lung squamous cell carcinoma
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DOI：
10.1038/s41374-021-00529-1
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发表时间：
2021-01-25
影响因子：
5
通讯作者：
Sakamoto, Noriaki
中科院分区：
文献类型：
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作者：
Kim, Yunjung;Shiba-Ishii, Aya;Sakamoto, Noriaki
患者来源的异种移植(PDX)小鼠模型被用于癌症的临床前研究，包括非小细胞肺癌(NSCLC)。尽管肺鳞状细胞癌(LUSCs)在非小细胞肺癌(NSCLC)中植入率最高，但其中一半在免疫缺陷小鼠中显示PDX失败。在这里，利用免疫组织化学和RNA测序，我们评估了显示成功植入的切除的LUSCs的独特的免疫组织化学和基因表达谱。在基本、经典、分泌型和原始亚型的LUSCs中，非移植组(NEG)的LUSCs基因表达谱类似于CK7阳性的单纯分泌型，而嫁接组(EG)的LUSCs类似于混合型的分泌型，P63阳性。对295个差异表达基因的通径分析表明，前者丰富了免疫系统相关基因的表达，而后者丰富了细胞周期和DNA复制相关基因的表达。有趣的是，NEG肿瘤的淋巴滤泡中B细胞(CD19(+))和滤泡树突状细胞(CD23(+))的浸润率高于EG肿瘤。综上所述，这些发现表明，LUSC的PDX癌症模型仅代表特定的LUSC群体，原始肿瘤中CD19和CD23阳性的肿瘤浸润性免疫细胞可能对免疫缺陷小鼠的PDX植入产生负面影响。患者衍生异种移植(PDX)模型是评估包括肺癌在内的癌症治疗的临床前和临床试验的有价值的平台。作者阐明，CD19和CD23等免疫系统相关基因的丰富表达是阻碍PDX生成的最关键因素，尤其是在肺鳞癌中。
Patient-derived xenograft (PDX) murine models are employed for preclinical research on cancers, including non-small cell lung cancers (NSCLCs). Even though lung squamous cell carcinomas (LUSCs) show the highest engraftment rate among NSCLCs, half of them nevertheless show PDX failure in immunodeficient mice. Here, using immunohistochemistry and RNA sequencing, we evaluated the distinct immunohistochemical and gene expression profiles of resected LUSCs that showed successful engraftment. Among various LUSCs, including the basal, classical, secretory, and primitive subtypes, those in the non-engrafting (NEG) group showed gene expression profiles similar to the pure secretory subtype with positivity for CK7, whereas those in the engrafting (EG) group were similar to the mixed secretory subtype with positivity for p63. Pathway analysis of 295 genes that demonstrated significant differences in expression between NEG and EG tumors revealed that the former had enriched expression of genes related to the immune system, whereas the latter had enriched expression of genes related to the cell cycle and DNA replication. Interestingly, NEG tumors showed higher infiltration of B cells (CD19(+)) and follicular dendritic cells (CD23(+)) in lymph follicles than EG tumors. Taken together, these findings suggest that the PDX cancer model of LUSC represents only a certain population of LUSCs and that CD19- and CD23-positive tumor-infiltrating immune cells in the original tumors may negatively influence PDX engraftment in immunodeficient mice.Patient-derived xenograft (PDX) models are valuable platforms to assess preclinical and clinical trials for cancer therapy including lung cancer. The authors clarified that enriched expression of immune system-associated genes such as CD19 and CD23 are the most critical factors to obstacle the PDX generation, particularly in lung squamous cell carcinoma.