Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Nature. 2018 Feb 1;554(7690):62-68. doi: 10.1038/nature25459. Epub 2018 Jan 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alleles
  • Animals
  • Carcinogenesis / genetics
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Disease Progression
  • Evolution, Molecular*
  • Female
  • Gene Dosage*
  • Genes, myc
  • Genes, p53
  • Humans
  • Male
  • Mice
  • Mutation
  • NF-kappa B p52 Subunit / genetics
  • Neoplasm Metastasis / genetics
  • Nuclear Proteins / genetics
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology*
  • Phenotype
  • Phosphoproteins / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Transcription Factors / genetics
  • Transcriptome / genetics
  • Transforming Growth Factor beta1 / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cdkn2a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • KRAS protein, human
  • NF-kappa B p52 Subunit
  • NFKB2 protein, human
  • Nfkb2 protein, mouse
  • Nuclear Proteins
  • Phosphoproteins
  • Transcription Factors
  • Transforming Growth Factor beta1
  • YY1AP1 protein, human
  • Yap protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)