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RNA-sequencing of whole lungs from mice with activating Kras mutations and epithelial Stat3 deletion

ABSTRACT: We have previously shown that Kras mutant-induced lung tumors in CCSPCre/LSL-K-rasG12D mice (CC-LR) exhibited Stat3 activation. Here we sought to study the role of epithelial Stat3 in Kras-mutant lung tumor oncogenesis through derivation of a lung epithelial specific CC-LR/Stat3 conditional knockout (LR/Stat3D/D or LRDD) model. Analysis of tumor burdens revealed marked gender disparity following epithelial Stat3 deletion, LRDD males exhibited increased tumor burdens compared to male CC-LR animals whereas female LRDD mice displayed attenuated tumor development when compared to female CC-LR littermates. We then performed RNA-sequencing of whole lungs from the mice in order to understand global expression programs that may underlie this gender-specific effect of epithelial Stat3 deletion.

ORGANISM(S): Mus musculus

PROVIDER: GSE109000 | GEO | 2018/12/26

REPOSITORIES: GEO

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Project description:Background: LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the aggressive cancer state that stems from Lkb1 deficiency can be reverted remains unknown. By bulk gene expression profiling, Lkb1 restoration promotes the expression of markers and functions of alveolar type II cells, suggesting that LKB1 may govern a cell-state transition within the neoplastic epithelial compartment. Purpose: To determine whether the restoration of Lkb1 drives changes in cell state and/or abundance within established oncogenic KRAS-driven lung tumors. Approach: To control LKB1 function in vivo, we generated an Lkb1XTR allele, which enables Cre-mediated disruption of Lkb1 expression during tumor development and subsequent FLPo-ERT2-mediated reactivation of Lkb1 within established tumors. Lung tumors were initiated in KT;Lkb1XTR/XTR (non-restorable) and KT;Lkb1XTR/XTR;FLPo-ERT2 (restorable) mice with Lenti-Cre. Following tumor development, lung tumor-bearing were treated with either corn oil vehicle or tamoxifen for two weeks prior to isolating specifically neoplastic cells by FACS for single cell RNA-seq. Results: Single cell analysis revealed that the neoplastic epithelial compartment was composed of alveolar type I- and type II-like subpopulations, a Krt8+ transitional state, an actively proliferating subpopulations, and an indeterminate subpopulation partially resembling the alveolar type II-like identity. Dynamic inference analyses indicated that the indeterminate population represents an intermediate state along the alveolar type II to alveolar type I trans-differentiation trajectory. Notably, the indeterminate cluster was more proliferative than the alveolar type II-like subpopulation and exhibited higher expression of Sox9, which is a marker of distal lung epithelial progenitors. There was a marked shift in the epithelial compartment from the indeterminate state to alveolar type II epithelial-like identity in response to Lkb1 restoration. Conclusions: LKB1 governs the transition between a proliferative progenitor-like population and mature alveolar type II-like identity within oncogenic KRAS-driven lung tumors

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RNA-sequencing of whole lungs from mice with activating Kras mutations and epithelial Stat3 deletion

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