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Series GSE179502 Query DataSets for GSE179502
Status Public on Dec 23, 2021
Title LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer [Sorted scRNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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
 
Overall design Lung tumors were initiated in KT;Lkb1XTR/XTR (non-restorable), and KT;Lkb1XTR/XTR;FLPo-ERT2 (restorable) mice with Lenti-Cre. Following tumor development and two weeks of treatment with either corn oil vehicle or tamoxifen, neoplastic cells were FACS-isolated from lung tumors and subjected to single cell RNA-seq.
 
Contributor(s) Murray C, Winslow M
Citation(s) 35228570
Submission date Jul 06, 2021
Last update date Mar 24, 2022
Contact name Christopher Murray
Organization name Stanford University
Department Genetics
Lab Winslow
Street address 1291 Welch Rd. B261, Beckman Center
City Stanford
State/province California
ZIP/Postal code 94305
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (6)
GSM5419465 CM0875
GSM5419466 CM0879
GSM5419467 CM0884
This SubSeries is part of SuperSeries:
GSE179560 LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
Relations
BioProject PRJNA744073
SRA SRP327105

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Supplementary file Size Download File type/resource
GSE179502_XTR_sorted_scRNAseq_barcodes.tsv.gz 406.7 Kb (ftp)(http) TSV
GSE179502_XTR_sorted_scRNAseq_depth_normalized.cloupe.gz 187.9 Mb (ftp)(http) CLOUPE
GSE179502_XTR_sorted_scRNAseq_features.tsv.gz 272.8 Kb (ftp)(http) TSV
GSE179502_XTR_sorted_scRNAseq_matrix.mtx.gz 182.5 Mb (ftp)(http) MTX
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Raw data are available in SRA
Processed data are available on Series record

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