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Series GSE231679 Query DataSets for GSE231679
Status Public on May 04, 2023
Title p53 governs an alveolar type 1 differentiation program in lung cancer suppression [in_vivo_RNA_seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Lung cancer is the leading cause of cancer deaths worldwide. TP53 tumor suppressor gene mutations occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, by promoting alveolar type 1 (AT1) differentiation. Using mice expressing oncogenic Kras and null, wild-type, or hypermorphic p53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA-sequencing and ATAC-sequencing of LUAD cells uncovered a p53-induced AT1 differentiation program during tumor suppression in vivo through direct DNA binding, chromatin remodeling, and AT1 gene induction. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 differentiation in alveolar injury repair. Notably, p53 inactivation resulted in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signaling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of p53wt and p53-null mice showed that p53 also directs alveolar regeneration after injury, by regulating AT2 self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumor suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.
 
Overall design Mouse lung cancer cells were isolated via FACS and analyzed via RNA-seq
 
Contributor(s) Kaiser AM, Attardi LD
Citation(s) 37468633
Submission date May 04, 2023
Last update date Aug 07, 2023
Contact name Laura D Attardi
E-mail(s) [email protected]
Organization name Stanford University
Lab Attardi
Street address 269 Campus Drive
City Stanford
State/province CA
ZIP/Postal code 94305
Country USA
 
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (11)
GSM7295773 KT, replicate 1, in vivo RNA-seq
GSM7295774 KT, replicate 2, in vivo RNA-seq
GSM7295775 KT, replicate 3, in vivo RNA-seq
This SubSeries is part of SuperSeries:
GSE231681 p53 governs an alveolar type 1 differentiation program in lung cancer suppression
Relations
BioProject PRJNA967292

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE231679_Bulk_RNA_seq_counts.xlsx 3.3 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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