Abstract A067: Myc drives phenotypic heterogeneity, metastasis, and therapy resistance in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAc) ranks among the top three most aggressive cancers in the United States and is projected to increase in incidence over the next few years. Standard of care treatment for PDAc consists of a cocktail of harsh chemotherapies, which have improved overall survival by only a few percentage points—to a 5-year survival rate of 11%. One commonly deregulated pathway in PDAc is c-MYC (MYC), a potent transcription factor. MYC plays an important role in tumor progression and its deregulation has been correlated with tumor aggressiveness and therapeutic resistance in PDAc and other cancers. Recently, oncogenic MYC expression has been shown to regulate elements of the tumor microenvironment (TME) in mouse models of multiple cancers. In PDAc, MYC’s expression has been linked to a desmoplastic immune suppressive TME, yet the specific mechanism has yet to be described. Here, we present a novel genetically engineered mouse model (GEMM) of PDAc that can be used to better model the disease and to interrogate questions of how MYC regulates the tumor immune and stromal microenvironments. Our KMCERT2 model has inducible Cre-driven expression of both mutant Kras and low deregulated Myc in the pancreas. We show that deregulated MYC cooperates with KRASG12D in the adult pancreas to drive PDAc, and our model recapitulates inter- and intra-tumoral heterogeneity seen within clinical PDAc populations. Currently, a majority of murine studies of PDAc are performed using an embryonic KrasG12D- and p53 loss/mutant-driven PDAc model (KPC). RNA- and DNA sequencing on both microdissected autochthonous tumor specimens and KMCERT2 tumor-derived cell lines was conducted to further understand the mechanisms underlying our observed phenotypes. In contrast to the KPC model, our inducible KMCERT2 model of PDAc displays genetic changes, such as CDKN2A and SMAD4 loss, comparable to human disease. Interestingly, multiplexed immunohistochemistry analysis of immune cell composition of spontaneous KMCERT2 tumors compared to the commonly used KPC shows an increased density of antigen presenting cells (APCs) within MYC-driven tumors. Human PDAc is often resistant to standard of care therapies such as gemcitabine and FOLFIRINOX. Orthotopic therapeutic studies using our KMCERT2 tumor-derived cell lines demonstrate a similar resistance to these therapies, allowing us to use this model to better understand the mechanisms leading to therapeutic resistance and to test new therapies. In addition, we find consistent metastasis to the liver in both spontaneous and orthotopic transplant settings. Together, this work investigates the role of deregulated MYC expression in metastatic behavior, immune phenotypes, and therapeutic response in murine PDAc. It also provides both spontaneous and orthotopic mouse models of PDAc that recapitulate the heterogeneous and highly metastatic nature of the human disease, allowing for important therapeutic testing opportunities. Citation Format: Isabel A. English, Patrick J. Worth, Amy S. Farrell, Brittany L. Allen-Petersen, Vidhi Shah, Courtney Betts, Carl Pelz, Xiaoyan Wang, Colin J. Daniel, Mary C Thoma, Lisa M Coussens, Ellen M Langer, Rosalie C Sears. Myc drives phenotypic heterogeneity, metastasis, and therapy resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A067.