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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE107458 | GEO | 2018/01/24

REPOSITORIES: GEO

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.

Project description:The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest KrasMUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains (Myc, Yap1 or Nfkb2), which collaborate with heterozygous KrasMUT in driving tumorigenesis, but have lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumour suppressor alterations (Cdkn2a, Trp53, Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of PDAC and shape its downstream biology. Our study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.

| S-EPMC6097607 | biostudies-literature

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes [aCGH]

Project description:Primary cell cultures were isolated from different KrasG12D-driven mouse models of pancreatic cancers and subjected to array comparative genomic hybridization (aCGH) for the investigation of copy number profiles.

2018-01-24 | GSE107454 | GEO

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes [expression]

Project description:Primary cell cultures were isolated from KrasG12D-driven, PiggyBac transposon-transposase pancreatic cancer cell cultures and subjected to microarray-based expression profiling for the investigation of expression profiles.

2018-01-24 | GSE107446 | GEO

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Bulk 3-prime transcript end RNA-Sequencing of KRASG12D- and GFP-overexpressing human pancreatic cancer cell lines.

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Bulk 3-prime transcript end RNA-Sequencing of KrasG12D-driven mouse pancreatic cancer cell cultures derived from primary pancreatic tumors (n=38).

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Bulk 3-prime transcript end RNA-Sequencing of epithelial/mesenchymal primary pancreatic cancer cell cultures enriched from a CRISPR/Cas9-edited, KrasG12D-driven mouse model of pancreatic cancer.

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Project description:Whole exome sequencing of KrasG12D-driven mouse pancreatic cancer cell cultures derived from primary pancreatic tumors (n=38) and liver or lung metastases (n=5).

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Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

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