Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1

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Nagaraj , A S , Lahtela , J , Hemmes , A , Pellinen , T , Blom , S , Devlin , J R , Salmenkivi , K , Kallioniemi , O , Mäyränpää , M , Narhi , K & Verschuren , E W 2017 , ' Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1 ' , Cell Reports , vol. 18 , no. 3 , pp. 673-684 . https://doi.org/10.1016/j.celrep.2016.12.059

Title: Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1
Author: Nagaraj, Ashwini S.; Lahtela, Jenni; Hemmes, Annabrita; Pellinen, Teijo; Blom, Sami; Devlin, Jennifer R.; Salmenkivi, Kaisa; Kallioniemi, Olli; Mäyränpää, Mikko; Narhi, Katja; Verschuren, Emmy W.
Contributor: University of Helsinki, University of Helsinki
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, University of Helsinki
University of Helsinki, University of Helsinki
University of Helsinki, University of Helsinki
University of Helsinki, HUSLAB
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUSLAB
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, University of Helsinki
Date: 2017-01-17
Language: eng
Number of pages: 12
Belongs to series: Cell Reports
ISSN: 2211-1247
URI: http://hdl.handle.net/10138/231826
Abstract: 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(G12D) 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.
Subject: HUMAN AIRWAY EPITHELIUM
K-RAS
SUPPRESSOR-CELLS
ADENOSQUAMOUS CARCINOMA
TISSUE MICROARRAY
TUMOR-SUPPRESSOR
CLARA CELLS
STEM CELLS
MOUSE LUNG
ADENOCARCINOMA
HISTOPATHOLOGY
LUNG CANCER
3111 Biomedicine
3122 Cancers
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