Abstract 2691: Extracellular adenosine signaling in pancreatic cancer: New therapeutic strategies

Abstract

Abstract Introduction: Approximately 90% of cancer-related deaths are due to tumor metastasis. Metastasis is a very complex process with several steps including cancer cell motility, invasion, circulation, extravasation, and metastatic colonization/outgrowth. For these diverse processes to take place, a cancer cell needs to acquire and maintain plasticity. Of relevance, a hallmark of metastatic initiation is the loss of membranous E-cadherin and the induction of the Epithelial to Mesenchymal Transition (EMT). During EMT, cancer cells not only exhibit protein expression changes, such as in E-cadherin, but also undergo dramatic reprogramming evident at the chromatin level. Elucidating mechanisms underlying metastasis is especially important in the context of pancreatic ductal adenocarcinoma (PDAC), as this lethal disease typically presents at metastatic stages. Using a PDAC mouse model whereby we endow the cells to undergo EMT, we find that metastatic capability is significantly augmented. We have utilized RNA sequencing from this model to elucidate underlying mechanisms of action and have prioritized CD73/Nt5e. CD73 is involved in the sensing and conversion of extracellular AMP to adenosine. The extracellular adenosine pathway has been shown to create an immunosuppressive environment, yet investigation of this pathway in the context of pancreatic cancer is lacking. Methods: To study the extracellular adenosine pathway in the context of PDAC, we use several different model systems including patient-derived 3D organoids, an autochthonous mouse model of pancreatic cancer (Pdx1-cre; LSL-KrasG12D/+; LSL-Trp53R172H; Rosa26LSL-YFP herein KPCY), and 2D cell culture. Results: We have been investigating the role of CD73 in PDAC and have uncovered novel cancer cell intrinsic and cell extrinsic roles. We demonstrate that CD73 is overexpressed in PDAC, and its overexpression is significantly associated with poor overall survival. Using our 3D organoids, we show that CD73 inhibition induces cell death. In addition, our CRISPR-Cas9 CD73 knockout lines have decreased metastatic abilities in vivo. Our preliminary work also suggests synergistic efficacy of anti-CD73 therapy when combined with inhibition of the adenosine receptors, Adora2a and Adora2b, which are related to CD73 biology. SUMMARY. Using a mouse model of PDAC with increased metastatic capability, we have unveiled the importance of CD73 expression and function in the context of PDAC. Our recent data suggests that CD73 activity has important roles, not only in the cancer cells but in other cells within the tumor microenviroment, and that targeting CD73 be very effective therapeutically. Citation Format: Anna M. Chiarella, Jason R. Pitarresi, Gulam Manji, Anil K. Rustgi. Extracellular adenosine signaling in pancreatic cancer: New therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2691.