Nagaraj Ashwini S, Lahtela Jenni, Hemmes Annabrita, Pellinen Teijo, Blom Sami, Devlin Jennifer R, Salmenkivi Kaisa, Kallioniemi Olli, Mäyränpää Mikko I, Närhi Katja, Verschuren Emmy W
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
HUSLAB, Division of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki 00029, Finland.
Cell Rep. 2017 Jan 17;18(3):673-684. doi: 10.1016/j.celrep.2016.12.059.
Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of Kras and loss of Lkb1 (Kras;Lkb1). Using progenitor cell-type-restricted adenoviral Cre to target cells expressing surfactant protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre-infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10 cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas. Transcriptome analysis shows ASC histotype-specific upregulation of pro-inflammatory and immunomodulatory genes. This is accompanied by an ASC-specific immunosuppressive environment, consisting of downregulated MHC genes, recruitment of CD11b Gr-1 tumor-associated neutrophils (TANs), and decreased T cell numbers. We conclude that progenitor cell-specific etiology influences the Kras;Lkb1-driven tumor histopathology spectrum and histotype-specific immune microenvironment.
肺癌表现出明显的功能异质性，这给精准医学带来了困扰。我们研究了细胞起源如何在Kras条件性表达和Lkb1缺失（Kras;Lkb1）后导致表型异质性。使用祖细胞类型受限的腺病毒Cre靶向表达表面活性蛋白C（SPC）或支气管肺泡灌洗细胞抗原10（CC10）的细胞，我们发现与Ad5-SPC-Cre组相比，Ad5-CC10-Cre感染的小鼠潜伏期更短。我们进一步证明，CC10细胞是腺鳞癌（ASC）肿瘤的主要祖细胞，并产生更广泛的组织学类型，包括黏液性和腺泡性腺癌。转录组分析显示ASC组织学类型特异性的促炎和免疫调节基因上调。这伴随着ASC特异性的免疫抑制环境，包括MHC基因下调、CD11b Gr-1肿瘤相关中性粒细胞（TANs）募集以及T细胞数量减少。我们得出结论，祖细胞特异性病因会影响Kras;Lkb1驱动的肿瘤组织病理学谱和组织学类型特异性免疫微环境。
