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 organization: University of Helsinki
Institute for Molecular Medicine Finland
Research Group Verschuren Emmy
Olli-Pekka Kallioniemi / Principal Investigator
HUSLAB
Medicum
Department of Pathology
Clinicum
Precision Systems Medicine
Lung Cancer Model Systems
Date: 2017-01-17
Language: eng
Number of pages: 12
Belongs to series: Cell Reports
ISSN: 2211-1247
DOI: https://doi.org/10.1016/j.celrep.2016.12.059
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
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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