Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy characterized by a profoundly immunosuppressive tumor microenvironment. Within PDAC, tumor-associated macrophages (TAMs) are the most abundant immune cell population. Here, TAMs orchestrate the characteristic immunosuppression of the pancreatic tumor microenvironment, drive disease progression, and mediate therapeutic resistance in PDAC. Accordingly, successful development of approaches that reprogram or eliminate these pro-tumor immune populations have potential to improve patient outcomes. One of the most challenging aspects of developing approaches to modulate TAMs programming is the ability to perform mechanistic experiments in a system the recapitulates the complex pancreatic tumor microenvironment. We and others have leveraged primary bone marrow-derived macrophages (BMDMs) polarized by PDAC conditioned media as a discovery platform that has yielded translational findings. However, this system fails to account for the dynamic and reciprocal interactions between myeloid and cancer cells that occur within tumors. Accordingly, we sought to address if this model could be built into progressively more complex systems to assess if these better recapitulate TAMs using a systems biology approach. Using transcriptomic profiling, we compared different in vitro strategies, from direct co-cultures to conditioned media polarization, against TAMs harvested from orthotopic PDAC tumors. Our preliminary data show that allowing PDAC cells to engage in direct cellular contact and sustained paracrine signaling most closely resemble the transcriptomic profile of bona fide TAMs. Our further efforts to use these PDAC-macrophage culture models will be key to identifying relevant signaling pathways that can be mechanistically examined prior to more cumbersome in vivo validation. Collectively, our data can be used to facilitate more accurate and insightful investigations into PDAC immunology and the development of therapeutic targeting strategies. Citation Format: Cavina K. Lee, Cecily Anaraki, Austin D. Silva, Tiffany Lai, Hillary Tran, Arjun Sapru. Dissecting myeloid - cancer communication networks in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr B104.
Lee et al. (2025) studied this question.