BioProject

Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. More...

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 proinflammatory and immunomodulatory genes. This is accompanied with 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. Overall design: Two tumors per mouse from three Kras;Lkb1 mice infected with Ad5-CC10-Cre, two tumors per mouse from three Kras;Lkb1 mice infected with Ad5-SPC-Cre, one tumour per mouse from two Kras;p53 mice infected with Ad5-CC10-Cre, and one tumour per mouse from three Kras;p53 mice infected with Ad5-SPC-Cre were analysed. Less...