Lahtela Jenni, Pradhan Barun, Närhi Katja, Hemmes Annabrita, Särkioja Merja, Kovanen Panu E, Brown Arthur, Verschuren Emmy W
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014, Finland.
Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki FI-00014, Finland.
Dis Model Mech. 2015 Apr;8(4):393-401. doi: 10.1242/dmm.019257. Epub 2015 Feb 20.
Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.
非小细胞肺癌（NSCLC）的治疗基于可靶向驱动癌基因的组织学分析和分子特征。治疗反应进一步由乘客突变情况或肿瘤抑制基因的缺失来定义。我们在此报告一项深入研究，以探讨推定的肺癌肿瘤抑制因子EPH受体A3（EPHA3）的生理作用，该基因在人类肺腺癌中经常发生突变。我们的数据表明，EphA3的纯合或杂合缺失不会改变由Kras突变或Trp53缺失导致的小鼠腺癌的进展，并且我们在成年野生型肺中检测到EphA3的出生后表达可忽略不计。然而，EphA3在发育中的小鼠肺的远端间充质中表达，与其Efna1配体的上皮表达相邻；这与EPH受体在胚胎发育中的已知作用一致。然而，EphA3的部分缺失仅导致上皮Nkx2-1、内皮Cd31和间充质Fgf10 RNA表达水平的细微变化，并且对肺上皮分支、间充质细胞增殖或CD31阳性内皮细胞的丰度和定位没有宏观表型影响。EphA3基因敲除小鼠中缺乏明显可辨的肺表型可能表明EPHA3在小鼠肺中缺乏明显作用，或者暗示EPH受体之间存在功能冗余。我们的研究展示了生物学复杂性如何挑战测序工作中鉴定的突变的体内功能验证，并为设计敲入或条件模型以确定EPHA3突变在肺肿瘤发生过程中的作用提供了动力。
