Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes

Abstract

The poor correlation of mutational landscapes with phenotypes limits our understanding of pancreatic ductal adenocarcinoma (PDAC) pathogenesis and metastasis. Here we show a critical role of oncogenic dosage-variation in PDAC biology and phenotypic diversification. We found gene-dosage increase of mutant KRASMUT in human PDAC precursors, driving both early tumorigenesis and metastasis, thus rationalizing early PDAC dissemination. To overcome limitations posed to gene-dosage studies by PDAC´s stroma-richness we developed large cell culture resources of metastatic mouse PDAC. Integration of their genomes, transcriptomes and tumor phenotypes with functional studies and human data, revealed additional widespread effects of oncogenic dosage-variation on cell morphology/plasticity, histopathology and clinical outcome, with 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, yet with lower metastatic potential. Mechanistically, different oncogenic gains and dosages evolve along distinct evolutionary routes, licensed by defined allelic states and/or combinations of hallmark tumor-suppressor alterations (Cdkn2a, Trp53, Tgfβ-pathway). Thus, evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive early progression and shape downstream PDAC biology. Our study uncovers universal principles in Ras-driven oncogenesis with potential relevance beyond pancreatic cancer.

Insulin promotes invasion and migration of KRASG12D mutant HPNE cells by upregulating MMP‐2 gelatinolytic activity via ERK‐ and PI3K‐dependent signalling

“…4 Previous studies revealed that the increasing KRAS mutation frequency correlated with the PanIN stage and it is nearly universal (>95%) in human PDAC. 6,7 Interestingly, in another mouse model with a KRAS G12V mutation, PanINs could be only induced if chronic inflammation and mutation existed at the same time. 6,7 Interestingly, in another mouse model with a KRAS G12V mutation, PanINs could be only induced if chronic inflammation and mutation existed at the same time.…”

The MAZ transcription factor is a downstream target of the oncoprotein Cyr61/CCN1 and promotes pancreatic cancer cell invasion via CRAF–ERK signaling

“…K-Ras mutations are the most prevalent in PDAC (20,30,47). It plays critical role in PDAC development and progression (30,50).…”

“…Multiple studies described the presence of an oncogenic K-Ras-signal is not sufficient for cellular transformation. Additional genetic, epigenetic, dosage or environmental factors may be required to raise the threshold of the activity of K-Ras signal for tumorigenesis (20,30,31), yet these factors have not been fully elucidated. A study has shown MAZ upregulates K-Ras transcription via binding into the G4-DNA of the K-Ras promoter in pancreatic cancer cells (7,32).…”

“…Several signature mutations are involved in PDAC progression. These include mutations in K-Ras and p53 tumor suppressor genes (15)(16)(17)(18)(19)(20)(21), deletion of p53, p61, SMAD4/DPC4 and deregulation of microRNAs (22)(23)(24) and chromosomal aberrations (25)(26)(27). Mutations in K-Ras gene are prevalent in PDAC and play critical, although poorly understood, roles in initiating and empowering progression of PDAC in human and genetically engineered mouse models in the presence of mutant p53 or absence of other tumor suppression genes (15,16,28,29).…”

“…Multiple studies described the presence of an oncogenic K-Ras-signal is not sufficient for cellular transformation. Additional genetic, epigenetic, dosage or environmental factors may be required to raise the threshold of the activity of K-Ras signal for tumorigenesis (20,30,31) CCN1/Cyr61 is a matricellular protein and a founder member of CCN (cyr61-CTGF-NOV)-family proteins (33)(34)(35). CCN1 is a tumor-promoting factor in PDAC (28,(36)(37)(38).…”