Source:Cell Reports, Volume 18, Issue 3
Author(s): Ashwini S. Nagaraj, Jenni Lahtela, Annabrita Hemmes, Teijo Pellinen, Sami Blom, Jennifer R. Devlin, Kaisa Salmenkivi, Olli Kallioniemi, Mikko I. Mäyränpää, Katja Närhi, Emmy W. Verschuren
Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell of origin contributes to phenotypic heterogeneity following conditional expression of KrasG12D 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.
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Nagaraj et al. demonstrate that the cell of origin defines the NSCLC histopathology spectrum and associated immune microenvironment upon the expression of KrasG12D and loss of the tumor suppressor Lkb1. Significantly, the histopathology rather than the oncogenotype determined immune signatures, suggesting that a deeper understanding of histotype-dependent features is important for clinical decision-making.from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2jJ78jg
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