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| Status |
Public on Apr 27, 2023 |
| Title |
Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas [ATAC-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
In pancreatic cancer, select cells within a homogeneous epithelium drive tumorigenesis in response to an environmental trigger, suggesting key uncharacterized roles for epigenetics and cellular context. To investigate epigenetic plasticity in early tumorigenesis, we performed single-cell transcriptional and chromatin accessibility sequencing of Kras-mutant pancreatic cancer models, encompassing initiation to malignant stages and wild-type tissue. Our analysis identifies a few progenitor states that correspond to known cells-of-origin, exhibit the greatest measured epigenetic plasticity, and are primed for diverse neoplastic fates. Plasticity is strongly associated with accessibility near receptor and ligand loci. We delineated robust communication modules and a feedback loop between IL33-expressing epithelial and immune cells with broad tissue impacts, which we confirmed by genetic perturbation in mice. Our results promise to nominate early interception strategies for this lethal cancer.
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| Overall design |
Characterization of single-cell chromatin accessibility (scATAC-seq) profiles of lineage-traced pancreatic epithelial cells (mKate2+) freshly-isolated by FACS-sorting from benign neoplasia (K3) or malignant (K5) pancreatic tissues: To characterize benign neoplasia (K3), KC;RIK (Ptf1a-Cre;RIK;LSLKrasG12D) mice were treated with caerulein at 5 weeks of age, and mKate2+ cells were subjected to scATAC-seq analyses 3 weeks thereafter. To characterize invasive disease (K5), pancreatic ductal adenocarcinoma (PDAC) cells were isolated from cancer lesions arising in autochthonous transgenic models (KPC;RIK (Ptf1a-Cre;RIK;LSL-KrasG12D;p53fl/+). Data from additional pre-malignant stages (K1, K2) were extracted from GSE137069, from KC-RIK mice treated with caerulein or PBS at 5 weeks of age, and analyzed 2 days thereafter. 2 biological replicates (independent mice) were used per experimental condition.
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| Contributor(s) |
Burdziak C, Alonso-Curbelo D, Pe'er D, Lowe SW |
| Citation(s) |
37167403 |
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| Submission date |
Jul 07, 2022 |
| Last update date |
Jun 02, 2023 |
| Contact name |
Cassandra Burdziak |
| E-mail(s) |
burdziac@mskcc.org
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Street address |
417 E 68th St
|
| City |
New York City |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE207943 |
Epigenetic plasticity cooperates with emergent cell-cell interactions to drive neoplastic tissue remodeling in the pancreas |
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| Relations |
| BioProject |
PRJNA856703 |
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