Abstract A17: The role of post-translational activation of MYC in pancreatic cancer development and progression
Authors: Farrell Amy S. , Daniel Colin J. , Jenny Zina , Sheppard Brett , Hooper Jody , Sears Rosalie C. 
Published: October 2015

Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States, with 46,420 new cases and 39,590 deaths estimated in 2014. Pancreatic cancer is a disease with a high rate of mortality, as it is generally diagnosed in the advanced stages when no curative treatments are available. Despite increased understanding of the morphology, biology, and molecular aberrations in pancreatic cancer, the 5-year survival rate has not improved significantly in the past 30 years.

The c-MYC (MYC) oncoprotein is a potent regulator of cell fate decisions that drives nearly all aspects of tumorigenesis, including tumor cell proliferation and tumor microenvironment remodeling. High levels of MYC expression occur in a wide variety of human tumors, and animal models demonstrate that MYC overexpression can drive tumorigenesis in many tissues. The MYC gene is frequently amplified in human pancreatic cancer and MYC mRNA and/or protein are often overexpressed. However, the role of MYC in pancreatic cancer development and progression is not well understood. Our laboratory has demonstrated that MYC is post-translationally activated by KRAS signaling. Specifically, the RAS-RAF-MEK-ERK signaling pathway leads to phosphorylation of MYC at Serine 62 (pS62-MYC), which increases MYC’s protein stability as well as its activation of oncogenic target gene expression. Furthermore, we have observed high expression of pS62-MYC in primary pancreatic tumors, starting as early as PanIN 1, compared to normal adjacent tissue. Since activating mutations in KRAS are an early and nearly universal event in the development of pancreatic ductal adenocarcinoma (PDAC), these data suggest that MYC may be a critical downstream effector of KRAS-driven pancreatic cancer.

We have generated unique c-MYC knock-in mice in which MYC is expressed from the ROSA26 locus following tissue-specific expression of Cre recombinase (ROSA-LSL-MYC). These mice express transcriptionally deregulated, but physiological levels of MYC. At these levels, however, MYCWT knock-in is not sufficient to drive tumors in any tested tissue. Since KRAS can post-translationally activate MYC, we hypothesized that low-level expression of deregulated MYC would increase KRAS driven pancreatic tumors in mice that co-express KRASG12D and MYCWT . We crossed ROSA-LSL-MYC mice with LSL-KRASG12D;Pdx1-Cre (KC) mice to generate the LSL-KRASG12D;ROSA-LSL-MYC;Pdx1-Cre (KMC) model. We found that co-expression of MYC and activated KRAS induces acinar to ductal metaplasia (ADM) and accelerates both PanIN precursor lesion formation and its conversion to PDAC relative to KRAS only. Tumors from KMC mice histologically resemble human PDAC, with a 20% metastatic rate to the liver. Together, these results suggest that MYC is important for both the initiation and progression of pancreatic tumors. In addition to ductal adenocarcinoma, the MYC/KRAS expressing mice also developed metastatic, poorly differentiated carcinomas with neuroendocrine features.

While activation of KRAS is thought to be one of the earliest oncogenic changes in PDAC-precursor cells, studies suggest that several other genetic events occur during the evolution of PanIN lesions to PDAC, including loss of p16, mutation/loss of p53, and loss of SMAD4. Importantly, tumors arising in our KMC model spontaneously exhibit these stage-appropriate molecular aberrations, suggesting that this model accurately recapitulates the genetic evolution of human pancreatic cancers. We also observe a strong desmoplastic reaction with prominent stroma and immune cell infiltration in these spontaneous pancreatic tumors. Thus, our novel KMC mice may provide a physiologically relevant model of human pancreatic cancer for the testing of new therapeutic agents.

Citation Format: Amy S. Farrell, Colin J. Daniel, Zina Jenny, Brett Sheppard, Jody Hooper, Rosalie C. Sears. The role of post-translational activation of MYC in pancreatic cancer development and progression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A17.