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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dc.contributor.author Nagaraj, Ashwini S.
dc.contributor.author Lahtela, Jenni
dc.contributor.author Hemmes, Annabrita
dc.contributor.author Pellinen, Teijo
dc.contributor.author Blom, Sami
dc.contributor.author Devlin, Jennifer R.
dc.contributor.author Salmenkivi, Kaisa
dc.contributor.author Kallioniemi, Olli
dc.contributor.author Mäyränpää, Mikko
dc.contributor.author Narhi, Katja
dc.contributor.author Verschuren, Emmy W.
dc.date.accessioned 2018-01-31T13:15:02Z
dc.date.available 2018-01-31T13:15:02Z
dc.date.issued 2017-01-17
dc.identifier.citation 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
dc.identifier.other PURE: 85907432
dc.identifier.other PURE UUID: a23baca5-6887-42e8-b2ea-3e9f0bf71929
dc.identifier.other WOS: 000396470600009
dc.identifier.other Scopus: 85009723984
dc.identifier.other ORCID: /0000-0002-1878-8911/work/41626119
dc.identifier.other ORCID: /0000-0002-0877-9640/work/41625614
dc.identifier.other ORCID: /0000-0001-5771-9129/work/41625496
dc.identifier.uri http://hdl.handle.net/10138/231826
dc.description.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. en
dc.format.extent 12
dc.language.iso eng
dc.relation.ispartof Cell Reports
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject K-RAS
dc.subject CLARA CELLS
dc.subject STEM CELLS
dc.subject MOUSE LUNG
dc.subject LUNG CANCER
dc.subject 3111 Biomedicine
dc.subject 3122 Cancers
dc.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 en
dc.type Article
dc.contributor.organization University of Helsinki
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Research Group Verschuren Emmy
dc.contributor.organization Olli-Pekka Kallioniemi / Principal Investigator
dc.contributor.organization HUSLAB
dc.contributor.organization Medicum
dc.contributor.organization Department of Pathology
dc.contributor.organization Clinicum
dc.contributor.organization Precision Systems Medicine
dc.contributor.organization Lung Cancer Model Systems
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.celrep.2016.12.059
dc.relation.issn 2211-1247
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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