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An epigenetic program established by gene – environment interactions initiates pancreatic carcinogenesis [Set3]

UID: 10944

Author(s): Alonso-Curbelo, Direna*, Lowe, Scott W.* * MSK affiliated

Description
Summary from GEO:

"Damaged tissues have increased risk of cancer development through poorly understood mechanisms. In the pancreas, tissue damage collaborates with activating mutations in the Kras oncogene to dramatically accelerate the formation of early neoplastic lesions and ultimately pancreatic cancer. By integrating genomics, single-cell chromatin assays and spatiotemporally-controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves large-scale chromatin accessibility changes that contribute to the early dysregulation of genes defining human pancreatic cancer. Among the genes most rapidly activated by tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine IL33, which cooperates with mutant Kras in unleashing the epigenetic remodeling program of early neoplasia and neoplastic transformation in the absence of injury. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene regulatory programs that dictate early neoplastic commitment and provides a molecular framework for understanding the interplay between genetics and environmental cues in cancer initiation."

Overall design from GEO:

"Characterization of the transcriptional profiles (RNA-seq) of bulk lineage-traced Kras-mutant pancreatic epithelial cells isolated by FACS-sorting from pancreata of Kras-mutant KC (p48-Cre;RIK;LSLKrasG12D) or Kras wild-type C (p48-Cre;RIK) mice treated with murine recombinant IL-33 (rIL-33) or PBS."
Subject of Study
Mus musculus
Subject(s)
Carcinogenesis
Epithelial Cells
Genes, ras
Genomics
Interleukin-33
Pancreatic Neoplasms
RNA-Seq
OncoTree Cancer Type(s)
Pancreatic Adenocarcinoma
Access via GEO


Accession #: GSE154543

Access via BioProject


Accession #: PRJNA646636

Access via SRA


Accession #: SRP272212

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA and BioProject databases provide open access to these files.
Associated Publications
Alonso-Curbelo D, Ho Y, Burdziak C, Maag J, Morris J, Chandwani R, Chen H, Tsanov K, Barriga F, Luan W, Tasdemir N, Livshits G, Azizi E, Chun J, Wilkinson J, Mazutis L, Leach S, Koche R, Pe’er D, Lowe S. A gene–environment-induced epigenetic program initiates tumorigenesis. Nature. 2021; 590(7847):642-648.
Equipment Used
Illumina HiSeq 2500

High throughput sequencing system

Dataset Format(s)
CSV
Dataset Size
4.9 MB
Data Catalog Record Updated
2023-10-16