Functional dissection of the role of Myc in Pancreatic tumorigenesis


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Nathiya Muthalagu1,Jennifer Morton1,Owen Sansom1,Daniel Murphy2
1Beatson Institute for cancer research,2University of Glasgow, Beatson Institute for cancer research

Abstract

Background

Non-resectable pancreatic ductal adenocarcinoma (PDAC) is presently an incurable disease with an estimated overall 5-year survival of less than 5%. Activating mutation of the small GTPase KRAS is found in up to 90% of all human PDACs, and CGH analyses of primary PDAC tumours revealed a high frequency of low-level amplification of chromosome 8q24, which includes the c-MYC locus. Recent studies using genetically engineered mouse models (GEMM) of PDAC suggested a crucial role for endogenous Myc in PDAC development. Here we aim to identify the mechanistic role of MYC in PDAC development. 

Method

Conditional alleles of LSL-KrasG12D and Rosa-26-LSL-MYC were targeted to pancreas using pancreas specific cre (Pdx1-Cre or Pdx1-CreER)

Results

The KrasG12D GEMM of pancreatic cancer has been previously reported to develop pancreatic intraepithelial neoplasms (PanINs) and rarely develop PDAC. Activation  of Rosa-MYC allele alone drives formation of PNETs but not to PanIN or PDAC.  However, when combined with the KrasG12D allele, we found that MYC co-operates with KrasG12D to accelerate progression to PDAC, both when activated in utero and when activated in the adult pancreas. Importantly, we show that modest deregulation of MYC is sufficient to drive pancreatic tumorigenesis as deletion of endogenous Myc prolonged the survival of KrasG12D/MYC driven pancreatic cancer mice.To understand the course of tumour evolution we made use of the Tamoxifen-inducible Cre fused to the Estrogen Receptor ligand-binding-domain (CreER) to activate both MYC and oncogenic Kras alleles in adult pancreata. Three  days of oncogene activation drives widespread proliferation and 14 days is sufficient to drive PanIN1. Also, superimposing MYC expression in mice with Kras induced PanINs is enough to overcome oncogene-induced senescence

Conclusion

Oncogene induced senescence is one of the major barrier preventing progression of Kras induced PanINs to PDAC and in this study we show that MYC overcomes oncogene-induced senescence.