Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [scATAC-seq]

ABSTRACT: Oncogenes are highly specific in the cells they can transform, although the molecular basis for this is poorly understood. Inflammation often promotes tumorigenesis, and in the pancreas it promotes cellular plasticity and accelerates Kras-driven neoplasia. We demonstrate that plasticity is coupled to the emergence of transient progenitor cells that are readily transformed by KrasG12D. The progenitor state is linked to coordinate upregulation of proliferation genes through chromatin opening at nearby lineage-specific enhancers. Mutant Kras taps into this program by co-opting the normally transient enhancer elements, making them permanent and Kras-dependent in cancer. Mechanistically, co-option occurs through cooperation of Kras-driven transcription factors with the existing landscape of pancreatic lineage transcription factors, which are recruited to play a central role in driving the mutant Kras-dependent transcriptional program. These observations suggest that proliferation is controlled by tissue-specific enhancer networks that are tapped into by oncogenes, helping explain the lineage specificity of cancer drivers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147726 | GEO | 2020/07/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [RNA-seq]

Project description:Oncogenes are highly specific in the cells they can transform, although the molecular basis for this is poorly understood. Inflammation often promotes tumorigenesis, and in the pancreas it promotes cellular plasticity and accelerates Kras-driven neoplasia. We demonstrate that plasticity is coupled to the emergence of transient progenitor cells that are readily transformed by KrasG12D. The progenitor state is linked to coordinate upregulation of proliferation genes through chromatin opening at nearby lineage-specific enhancers. Mutant Kras taps into this program by co-opting the normally transient enhancer elements, making them permanent and Kras-dependent in cancer. Mechanistically, co-option occurs through cooperation of Kras-driven transcription factors with the existing landscape of pancreatic lineage transcription factors, which are recruited to play a central role in driving the mutant Kras-dependent transcriptional program. These observations suggest that proliferation is controlled by tissue-specific enhancer networks that are tapped into by oncogenes, helping explain the lineage specificity of cancer drivers.

2020-07-11 | GSE134235 | GEO

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [ChIP-seq]

2020-07-11 | GSE134233 | GEO

Mutant Kras co-opts a progenitor-derived enhancer network to initiate pancreatic tumorigenesis [ATAC-seq]

2020-07-11 | GSE134230 | GEO

Myc regulates the lineage commitment of transformed hepatocytes during liver tumorigenesis (RNA-Seq)

Project description:The two oncogenes Myc and Kras cooperate to drive tumorigenesis and tumor suppressive pathways, to regulate the tumor microenvironment and to respond to immuno-therapies in different types of cancer. However, the interactions between Myc and Kras in cancer plasticity remain largely unknown. Primary liver cancer (PLC) comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), two tumor subtypes which are morphologically and clinically different, and cell intrinsic molecular mechanisms that lead to the onset of HCC or ICC remain elusive. Here using a mouse model of KrasG12D-driven ICC we show that Myc overexpression switches the tumorigenesis towards HCC. Lineage tracing experiments showed that this switch occurred in KrasG12D transformed hepatocyte fated to develop into ICC. Since cell fate decisions during lineage differentiation are coordinately regulated by transcriptional and epigenetic changes, we took advantage of transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiling to analyze hepatocytes transformed either with KrasG12D only or with KrasG12D and Myc. We identified Foxa1, Foxa2 and Ets1 as the major transcription factors responsible of the lineage commitment of transformed hepatocytes towards ICC or HCC, a function that is conserved also in humans. Altogether, our study describes an unanticipated cell intrinsic mechanism of lineage determination during the development of primary liver cancer orchestrated by the oncogene Myc.

2023-07-24 | GSE156744 | GEO

Myc regulates the lineage commitment of transformed hepatocytes during liver tumorigenesis (ATAC-Seq)

2023-07-24 | GSE156743 | GEO

Differences in gynecologic tumor development in Amhr2-Cre mice with KRASG12D or KRASG12V mutations

Project description:We report the RNAseq data from uterine tissues obtained from mice that over-express KRAS-G12D or KRAS-G12V oncogenes in a Ahmr2-Cre Pten null genetic background.

2020-04-01 | GSE129520 | GEO

Overcoming Lineage Plasticity and AR-Targeted Therapy Resistance in ZNF397-Deficient Prostate Cancer via TET2 Inhibition [RNA-seq]

Project description:Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offers promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

2024-04-05 | GSE230601 | GEO

Overcoming Lineage Plasticity and AR-Targeted Therapy Resistance in ZNF397-Deficient Prostate Cancer via TET2 Inhibition [ChIP-seq]

2024-04-05 | GSE230600 | GEO

Overcoming Lineage Plasticity and AR-Targeted Therapy Resistance in ZNF397-Deficient Prostate Cancer via TET2 Inhibition [ATAC-seq]

2024-04-05 | GSE260467 | GEO

Overcoming Lineage Plasticity and AR-Targeted Therapy Resistance in ZNF397-Deficient Prostate Cancer via TET2 Inhibition [5hmC-seq]

2024-04-05 | GSE260466 | GEO