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.
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 KrasG12Dand 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.
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Ashwini S
authors.initials: AS
authors.lastname: Nagaraj
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Lahtela
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Annabrita
authors.initials: A
authors.lastname: Hemmes
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Teijo
authors.initials: T
authors.lastname: Pellinen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Blom
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Devlin
authors.affiliation: HUSLAB, Division of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki 00029, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Salmenkivi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland; Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 17165 Solna, Sweden.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: HUSLAB, Division of Pathology, Helsinki University Hospital and University of Helsinki, Helsinki 00029, Finland; Department of Pathology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Mäyränpää
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland.
authors.forename: Katja
authors.initials: K
authors.lastname: Närhi
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00014, Finland. Electronic address: emmy.verschuren@helsinki.fi.
authors.forename: Emmy W
authors.initials: EW
authors.lastname: Verschuren
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014598:Uteroglobin / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; C556390:Scgb1a1 protein, mouse; D016159:Tumor Suppressor Protein p53; D014598:Uteroglobin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C544448:Arg1 protein, mouse; D001119:Arginase; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; Lkb1; adenosquamous; cell-of-origin; club cell; histopathology; immune microenvironment; non-small-cell lung cancer; tumor-associated neutrophils