Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

被引：312

作者：

Mueller, Sebastian ^{[1
,2
]}

Engleitner, Thomas ^{[1
,2
,3
]}

Maresch, Roman ^{[1
,2
,3
]}

Zukowska, Magdalena ^{[1
,2
]}

Lange, Sebastian ^{[1
,2
]}

Kaltenbacher, Thorsten ^{[1
,2
,3
]}

Konukiewitz, Bjoern ^{[4
]}

Oellinger, Rupert ^{[1
,2
]}

Zwiebel, Maximilian ^{[2
]}

Strong, Alex ^{[5
]}

Yen, Hsi-Yu ^{[3
,6
]}

Banerjee, Ruby ^{[5
]}

Louzada, Sandra ^{[5
]}

Fu, Beiyuan ^{[5
]}

Seidler, Barbara ^{[1
,2
]}

Goetzfried, Juliana ^{[2
]}

Schuck, Kathleen ^{[2
]}

Hassan, Zonera ^{[2
]}

Arbeiter, Andreas ^{[2
]}

Schoenhuber, Nina ^{[1
,2
]}

Klein, Sabine ^{[1
,2
]}

Veltkamp, Christian ^{[1
,2
]}

Friedrich, Mathias ^{[5
]}

Rad, Lena ^{[2
]}

Barenboim, Maxim ^{[2
,3
]}

Ziegenhain, Christoph ^{[7
]}

Hess, Julia ^{[8
]}

Dovey, Oliver M. ^{[5
]}

Eser, Stefan ^{[2
]}

Parekh, Swati ^{[7
]}

Constantino-Casas, Fernando ^{[9
]}

de la Rosa, Jorge ^{[5
,10
,11
]}

Sierra, Marta I. ^{[12
]}

Fraga, Mario ^{[12
,13
]}

Mayerle, Julia ^{[14
]}

Kloeppel, Gunter ^{[4
]}

Cadinanos, Juan ^{[5
,10
]}

Liu, Pentao ^{[5
]}

Vassiliou, George ^{[5
]}

Weichert, Wilko ^{[3
,4
]}

Steiger, Katja ^{[4
,6
]}

Enard, Wolfgang ^{[7
]}

Schmid, Roland M. ^{[2
,3
]}

Yang, Fengtang ^{[5
]}

Unger, Kristian ^{[8
]}

Schneider, Gunter ^{[2
,3
]}

Varela, Ignacio ^{[15
]}

Bradley, Allan ^{[5
]}

Saur, Dieter ^{[1
,2
,3
]}

Rad, Roland ^{[1
,2
,3
]}

机构：

[1] Tech Univ Munich, Ctr Translat Canc Res TranslaTUM, D-81675 Munich, Germany

[2] Tech Univ Munich, Dept Med 2, Klinikum Rechts Isar, D-81675 Munich, Germany

[3] German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[4] Tech Univ Munich, Inst Pathol, D-81675 Munich, Germany

[5] Wellcome Trust Sanger Inst, Genome Campus, Cambridge CB10 1SA, England

[6] Tech Univ Munich, Comparat Expt Pathol, D-81675 Munich, Germany

[7] Univ Munich, Dept Biol 2, Anthropol & Human Genom, D-82152 Martinsried, Germany

[8] Helmholtz Zentrum Munchen, Res Unit Radiat Cytogenet, D-85764 Neuherberg, Germany

[9] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England

[10] IMOMA, Oviedo 33193, Spain

[11] Univ Oviedo, Inst Univ Oncol IUOPA, Fac Med, Dept Bioquim & Biol Mol, Oviedo 33006, Spain

[12] Univ Oviedo, Inst Oncol Asturias IUOPA, HUCA, Oviedo 33011, Spain

[13] Univ Oviedo, Nanomat & Nanotechnol Res Ctr CINN CSIC, El Entrego 33940, Spain

[14] Klinikum LMU Munchen Grosshadern, Med Klin & Poliklin 2, D-81377 Munich, Germany

[15] Inst Biomed & Biotecnol Cantabria UC CSIC, Santander 39012, Spain

来源：

NATURE | 2018年 / 554卷 / 7690期

基金：

欧洲研究理事会;

关键词：

EXPRESSION; TUMOR; MUTATIONS; CARCINOMA; SUBTYPES; CELLS; MODEL; P53; CLASSIFICATION; AMPLIFICATIONS;

D O I：

10.1038/nature25459

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, Tgf beta-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.

引用

页码：62 / +

页数：28

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