|
| Status |
Public on Dec 23, 2021 |
| Title |
LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer [C/EBP Bulk RNA-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. Restoration of Lkb1 in established lung tumors promotes the expression of C/EBP target genes as well as features of alveolar type II cell differentiation, which requires the activity of C/EBP transcription factors in the developmental setting. Purpose: To determine the extent to which the disruption of C/EBP transcription factors recapitulates the transcriptional changes induced by the inactivation of Lkb1.Approach: To assess the changes gene expression induced by CRISPR/Cas9-mediated disruption of either C/EBP transcription factors or Lkb1, we induced lung tumors in KrasLSL-G12D/+;R26LSL-tdTomato;H11LSL-Cas9 mice using Lenti-sgNeo1/sgNT/sgNeo2/Cre (sgInert), Lenti-sgLkb1/Cre (sgLkb1), or Lenti-sgCebpa/sgCebpb/sgCebpd/Cre (sgCebpa/b/d). Neoplastic cells were then isolated from lung tumors by FACS for gene expression profiling by RNA-seq. Results: The disruption of C/EBP transcription factors partially recapitulates the gene expression changes induced by Lkb1 inactivation. Among the genes that are jointly dependent upon C/EBP transcription factors and LKB1 is an enrichment of NKX2-1-dependent target genes. Conclusions: C/EBP transcription factors likely operate downstream of LKB1 in an indirect manner, collaborating with another key developmental regulator, NKX2-1, to enforce alveolar type II cell differentiation to constrain tumor growth.
|
| |
|
| Overall design |
Lung tumors were initiated in KrasLSL-G12D/+;R26LSL-tdTomato;H11LSL-Cas9 mice with Lenti-sgNeo1/sgNT/sgNeo2/Cre (sgInert), Lenti-sgLkb1/Cre (sgLkb1), or Lenti-sgCebpa/sgCebpb/sgCebpd/Cre (sgCebpa/b/d). Following tumor development, neoplastic cells were FACS-isolated from lung tumors and subjected to bulk 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) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (19)
|
|
| 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 |
PRJNA744200 |
| SRA |
SRP327177 |
Less...
More...