TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice

Studies have shown that Nrf2E79Q/+ is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2E79Q/+. Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2E79Q mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2+/+ mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2E79Q allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2E79Q mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE+-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development.

研究表明，Nrf2E79Q/+是人类肿瘤中最常见的突变类型之一。为阐明该遗传改变如何促进肺癌发生，本研究采用携带双Trp53/p16缺失（人类肺癌最常见的突变组合）的基因工程小鼠模型（genetically-engineered mouse model，GEMM），分别在存在或缺失Nrf2E79Q/+的条件下，比较两组小鼠的肺肿瘤发生情况。缺失Trp53/p16的小鼠会形成复合性小细胞肺癌（combined-small cell lung cancer，C-SCLC），该肿瘤由单纯性小细胞肺癌（pure-SCLC，P-SCLC）与大细胞神经内分泌癌混合构成。携带LSL-Nrf2E79Q突变的小鼠，其C-SCLC的发生率与发病潜伏期与Nrf2+/+小鼠无显著差异。然而，尽管Cre酶介导了LSL-Nrf2E79Q等位基因的重组，这些肿瘤并未表达NRF2蛋白。缺失Trp53/p16的小鼠还会形成单纯性小细胞肺癌，此时NRF2E79Q突变的激活与该肿瘤类型的更高发生率相关。所有C-SCLC与P-SCLC均呈神经内分泌标志物（NE-markers）、肺癌标志物NKX1-2阳性，而鳞状细胞标志物P63阴性；仅P-SCLC经免疫组化检测可表达NRF2。对人类神经内分泌阳性肺癌的共识性NRF2通路特征基因集进行分析，结果显示NRF2信号通路的激活程度存在异质性。本研究首次构建了可形成复合性小细胞肺癌的基因工程小鼠模型，而复合性小细胞肺癌是一种研究较为匮乏的人类恶性肿瘤；本研究同时揭示了NRF2激活在小细胞肺癌发生发展中的潜在作用。