Abstract B014: Leveraging dynamic epigenetic landscapes to decode tumor-associated macrophages in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with 90% of patients developing resistance to standard chemotherapy, such as gemcitabine/paclitaxel protein-bound (GnP). PDAC tumors are characteristically immunosuppressive and fibrotic due to programs activated in tumor-associated macrophages (TAMs) and their crosstalk with cancer-associated fibroblasts. These harsh tumor conditions contribute to the therapeutic resistance observed in patients. Preclinical studies demonstrate blockade of signaling pathways in PDAC TAMs can induce macrophage reprogramming to support antitumor response and restore chemosensitivity in tumors. Yet, their translation to the clinic has had minimal benefit in improving patient survival, particularly due to the persistence of macrophage reprogramming. If the PDAC microenvironment is to be effectively remodeled by altering TAM functionality to improve therapeutic outcomes, it is critical to understand the upstream, epigenetic regulatory mechanisms driving these different PDAC macrophages states that enable tumor progression and chemoresistance. Our work into tissue macrophages has demonstrated the transcription factor MITF strongly regulates how macrophages respond to environmental signals. Specifically, MITF binding to gene enhancers, which are DNA regions that instruct when genes are expressed, is upregulated, leading to activation of MITF-dependent genes, which are found among immunosuppressive macrophage programs. Leveraging the MITF-dependent gene signature activated in macrophages, we sought to address how MITF-associated enhancers are mechanistically influencing PDAC TAM functions as the tumor becomes more advanced and develops chemoresistance. The MITF-dependent gene signature is enriched in TAM subsets from both human PDAC and PDAC tumors from KPC (Kras +/LSL-G12D;Trp53 +/LSL-R172H;Pdx1-Cre) mice, suggesting that in part, PDAC TAMs may depend on MITF-associated enhancers. We are now processing murine parental and GnP chemotherapy-resistant tumors through a single-nuclei paired-tag omics approach to simultaneously evaluate gene expression and histone modification H3K27ac at the single cell level. This work will provide a multi-omics view of the epigenetic landscape in therapy-resistant PDAC, which will be critical to identify relevant MITF-associated enhancers that are modulated in TAMs during resistance prior to in vivo validation. Overall, our data will inform how epigenetic mechanisms are directly linked to establishing different TAM states in PDAC to facilitate novel therapeutic targets that can remodel the PDAC microenvironment and improve response to existing therapies.