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| Status |
Public on Aug 08, 2023 |
| Title |
Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [Nanostring] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.
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| Overall design |
For miRNA expression assay, lung tumors from KrasLA1/+;Dicer1S2D/+ mice (n=5) were compared to lung tumors from Kras LA1/+ mice (n=4). KrasLA1 mouse model have an oncogenic Kras G12D mutation. And KrasLA1/+;Dicer1S2D/+ have a heterozygous phosphomimetic Dicer1 in where serienes 1712 and 1836 were replaced to aspartic acid, in a heterozygous Kras LA1 oncogenic background. For this experiment, 30 to 37 weeks old mice from both genotypes were used. A total of 50mg of lung tumors per mouse was used and 577 miRNAs were analyzed using Nanostring nCounter mouse miRNA array..
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| Contributor(s) |
Reyes-Castro RA, Chen S, Seemann J, Lozano G, Arur S |
| Citation missing |
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| Submission date |
Apr 04, 2023 |
| Last update date |
Aug 09, 2023 |
| Contact name |
Raisa Reyes-Castro |
| E-mail(s) |
RAReyes2@mdanderson.org
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| Organization name |
UT Health MD Anderson Cancer Center
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| Department |
Genetics
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| Lab |
Swathi Arur
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| Street address |
6767 Bertner Ave
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| City |
Houston |
| State/province |
Texas |
| ZIP/Postal code |
77030 |
| Country |
USA |
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| Platforms (1) |
| GPL33314 |
nCounter Nanostring mouse miRNA (NS_M_MIR_V1.5) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE228968 |
Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas |
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| Relations |
| BioProject |
PRJNA952253 |
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