Journal Article

Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Sierra, Marta I., Parekh, Swati, Banerjee, Ruby, Saur, Dieter, Schmid, Roland M., Schuck, Kathleen, Engleitner, Thomas, Yang, Fengtang, Lange, Sebastian, Louzada, Sandra, Fu, Beiyuan, Rad, Lena, Ziegenhain, Christoph, Kaltenbacher, Thorsten, Bradley, Allan, Constantino-Casas, Fernando, Steiger, Katja, Unger, Kristian, Zukowska, Magdalena, Klöppel, Günter, Barenboim, Maxim, Fraga, Mario, Rad, Roland, Veltkamp, Christian, de la Rosa, Jorge, Eser, Stefan, Hassan, Zonera, Cadiñanos, Juan, Konukiewitz, Björn, Zwiebel, Maximilian, Yen, Hsi-Yu, Enard, Wolfgang, Friedrich, Mathias, Götzfried, Juliana, Schneider, Günter, Weichert, Wilko, Hess, Julia, Mayerle, Julia, Dovey, Oliver M., Strong, Alex, Seidler, Barbara, Öllinger, Rupert, Mueller, Sebastian, Klein, Sabine, Arbeiter, Andreas, Schönhuber, Nina, Liu, Pentao, Varela, Ignacio, Maresch, Roman, Vassiliou, George

2018

Overview

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 Kras MUT levels underlying aggressive undifferentiated phenotypes. We also identify alternative oncogenic gains ( Myc , Yap1 or Nfkb2 ), which collaborate with heterozygous Kras MUT 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. Oncogenic dosage variation along distinct evolutionary routes defines fundamental aspects of pancreatic cancer biology and phenotypic diversification. Predicting pancreatic cancer phenotypes Despite the availability of hundreds of pancreatic cancer genomes, it has been difficult to associate specific mutation patterns with distinct biological features. To address this, Roland Rad and colleagues tracked genomic alterations during the development of pancreatic cancer, aiming to link mutations to heterogeneous phenotypes. Human and mouse studies reveal that different gene dosages of an activating KRAS mutation are critical determinants of pancreatic cancer biology, including early progression, metastasis, histopathology, cellular plasticity and clinical aggressiveness. Mutant KRAS is amplified through distinct evolutionary routes during tumorigenesis that are defined by prior alterations of specific tumour suppressors and oncogenes. This study sheds light on the mechanisms underlying the phenotypic heterogeneity of pancreatic cancer and may aid advances in diagnosis, prognosis and therapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/39 / 38/70 / 38/91 / 45/22 / 45/23 / 45/90 / 631/67/1504/1713 / 631/67/69 / 631/67/70 / 64/110 / Adaptor Proteins, Signal Transducing - genetics / Adenocarcinoma / Alleles / Animals / Biological research / Carcinogenesis - genetics / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - pathology / Cell culture / Cell Cycle Proteins / Cell morphology / Chromosomes / Cyclin-Dependent Kinase Inhibitor p16 - genetics / Cytology / Disease Progression / Evolution / Evolution, Molecular / Female / Gene Dosage / Genes / Genes, myc / Genes, p53 / Genetic aspects / Genomes / Genomics / Genotype & phenotype / Histopathology / Humanities and Social Sciences / Humans / K-Ras protein / Male / Metastases / Metastasis / Mice / multidisciplinary / Mutation / Myc protein / Neoplasm Metastasis - genetics / NF-kappa B p52 Subunit - genetics / Nuclear Proteins - genetics / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Pathogenesis / Phenotype / Phenotypes / Phosphoproteins - genetics / Physiological aspects / Proto-Oncogene Proteins p21(ras) - genetics / Science / Transcription Factors - genetics / Transcriptome - genetics / Transforming Growth Factor beta1 - genetics / Tumorigenesis / Tumors / YAP-Signaling Proteins / Yes-associated protein