TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.
TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice.
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DOI：
10.1038/s41388-022-02348-0
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发表时间：
2022-06
期刊：
影响因子：
8
通讯作者：
Weissman, Bernard E.
中科院分区：
文献类型：
--
作者：
Hamad, Samera H.;Montgomery, Stephanie A.;Simon, Jeremy M.;Bowman, Brittany M.;Spainhower, Kyle B.;Murphy, Ryan M.;Knudsen, Erik S.;Fenton, Suzanne E.;Randell, Scott H.;Holt, Jeremiah R.;Hayes, D. Neil;Witkiewicz, Agnieszka K.;Oliver, Trudy G.;Ben Major, M.;Weissman, Bernard E.
研究表明，Nrf 2 E79 Q/+是人类肿瘤中最常见的突变之一。为了阐明这种遗传变化如何导致肺癌，我们比较了在存在或不存在Nrf 2 E79 Q/+的情况下，在具有Trp 53/p16双缺失的基因工程小鼠模型（GEMM）中的肺肿瘤发展，这是在人类肺肿瘤中发现的最常见的突变。Trp 53/p16缺陷小鼠发生了混合型小细胞肺癌（C-SCLC），即纯SCLC（P-SCLC）和大细胞神经内分泌癌的混合物。与Nrf 2 +/+小鼠相比，具有LSL-Nrf 2 E79 Q突变的小鼠在C-SCLC的发病率或潜伏期方面没有差异。然而，这些肿瘤不表达NRF 2，尽管Cre诱导的LSL-Nrf 2 E79 Q等位基因重组。Trp 53/p16缺陷小鼠也发生P-SCLC，其中NRF 2 E79 Q突变的激活与该肿瘤类型的较高发生率相关。所有C-SCLC和P-SCLC均对NE标记物NKX 1 -2（肺癌标记物）呈阳性，对P63（鳞状细胞标记物）呈阴性，而仅P-SCLC通过免疫组织化学表达NRF 2。在人NE+-肺肿瘤中的共有NRF 2通路签名的分析显示NRF 2信号传导的可变激活。我们的研究描述了第一个发展C-SCLC的GEMM，这是一种研究不足的人类癌症，并暗示了NRF 2激活在SCLC发展中的作用。
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.
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影响因子：
11.2
作者：
Laddha, Saurabh V.;da Silva, Edaise M.;Chan, Chang S.
通讯作者：
Chan, Chang S.
影响因子：
16.6
作者：
Fernandez-Cuesta, Lynnette;Peifer, Martin;Lu, Xin;Sun, Ruping;Ozretic, Luka;Seidel, Danila;Zander, Thomas;Leenders, Frauke;George, Julie;Mueller, Christian;Dahmen, Ilona;Pinther, Berit;Bosco, Graziella;Konrad, Kathryn;Altmueller, Janine;Nuernberg, Peter;Achter, Viktor;Lang, Ulrich;Schneider, Peter M.;Bogus, Magdalena;Soltermann, Alex;Brustugun, Odd Terje;Helland, Aslaug;Solberg, Steinar;Lund-Iversen, Marius;Ansen, Sascha;Stoelben, Erich;Wright, Gavin M.;Russell, Prudence;Wainer, Zoe;Solomon, Benjamin;Field, John K.;Hyde, Russell;Davies, Michael P. A.;Heukamp, Lukas C.;Petersen, Iver;Perner, Sven;Lovly, Christine M.;Cappuzzo, Federico;Travis, William D.;Wolf, Juergen;Vingron, Martin;Brambilla, Elisabeth;Haas, Stefan A.;Buettner, Reinhard;Thomas, Roman K.
通讯作者：
Thomas, Roman K.
影响因子：
16.6
作者：
George J;Walter V;Peifer M;Alexandrov LB;Seidel D;Leenders F;Maas L;Müller C;Dahmen I;Delhomme TM;Ardin M;Leblay N;Byrnes G;Sun R;De Reynies A;McLeer-Florin A;Bosco G;Malchers F;Menon R;Altmüller J;Becker C;Nürnberg P;Achter V;Lang U;Schneider PM;Bogus M;Soloway MG;Wilkerson MD;Cun Y;McKay JD;Moro-Sibilot D;Brambilla CG;Lantuejoul S;Lemaitre N;Soltermann A;Weder W;Tischler V;Brustugun OT;Lund-Iversen M;Helland Å;Solberg S;Ansén S;Wright G;Solomon B;Roz L;Pastorino U;Petersen I;Clement JH;Sänger J;Wolf J;Vingron M;Zander T;Perner S;Travis WD;Haas SA;Olivier M;Foll M;Büttner R;Hayes DN;Brambilla E;Fernandez-Cuesta L;Thomas RK
通讯作者：
Thomas RK
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A