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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 04, 2023 |
| Title |
p53 governs an alveolar type 1 differentiation program in lung cancer suppression [10x_multiome_ATAC] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| 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.
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| Overall design |
Mouse lung cancer cells were isolated via FACS and analyzed via 10x single cell multiomics ATAC
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| Contributor(s) |
Kaiser AM, Hanson KJ, Attardi LD |
| Citation(s) |
37468633 |
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| Submission date |
May 04, 2023 |
| Last update date |
Aug 07, 2023 |
| Contact name |
Laura D Attardi |
| E-mail(s) |
[email protected]
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| Organization name |
Stanford University
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| Lab |
Attardi
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| Street address |
269 Campus Drive
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| GSM7295720 |
KT, replicate 1, 10x multiome ATAC-Seq |
| GSM7295721 |
KT, replicate 2, 10x multiome ATAC-Seq |
| GSM7295722 |
KPT, replicate 1, 10x multiome ATAC-Seq |
| GSM7295723 |
KPT, replicate 2, 10x multiome ATAC-Seq |
| GSM7295724 |
KFT, replicate 1, 10x multiome ATAC-Seq |
| GSM7295725 |
KFT, replicate 2, 10x multiome ATAC-Seq |
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| This SubSeries is part of SuperSeries: |
| GSE231681 |
p53 governs an alveolar type 1 differentiation program in lung cancer suppression |
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| Relations |
| BioProject |
PRJNA967276 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE231671_RAW.tar |
2.8 Gb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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