Abstract 2551: Aged microenvironments promote liver metastasis in pancreatic ductal adenocarcinoma

Abstract Advancing age is the strongest independent risk factor for developing pancreatic ductal adenocarcinoma (PDAC). Older patients are more likely to present with advanced stage disease and have inferior overall survival when liver metastases are present. There is a critical need to understand the molecular factors that promote PDAC metastasis in order to guide development of more effective therapies. Despite the strong association of PDAC incidence and liver metastasis with aging, mechanisms through which aging impacts this process are not understood. Our prior work identified age-related changes in the PDAC tumor microenvironment (TME) that promote orthotopic PDAC tumor growth in aged (>12-month-old) compared to young (8-week-old) mice. GDF-15, a divergent TGFβ superfamily member, is a critical factor released by aged fibroblasts in the TME that promotes PDAC growth in an age-dependent fashion. We have recently identified that liver metastases are significantly more frequent in aged hosts, consistent with clinical observations. To determine how aging promotes PDAC metastases, we performed studies using novel human and mouse models that incorporate age as a variable. Primary tumors from aged mice have increased angiogenesis and decreased CD8+ T cell infiltration, findings associated with metastasis. To determine if GDF-15, released at high levels by aged but not young pancreatic fibroblasts, is involved in priming tumors for metastasis, we performed recombinant GDF-15 treatment of young mice harboring orthotopic KPC tumors. We found that GDF-15 significantly increases angiogenesis and decreases CD8+ T cell infiltration, changes associated with increased likelihood of metastasis. Tumors in aged GDF-15 knock out mice give rise to fewer metastases and have decreased angiogenesis and CD8+ T cell infiltration compared to aged wild type mice. Treatment of both human and mouse pancreatic cancer cells in vitro with aged fibroblast conditioned media or recombinant GDF-15 results in increased migration and invasion driven by GDF-15 specific activation of AKT signaling relative to controls. We next tested if the aged liver, independently of effects in a primary tumor, contributes to metastasis. Portal vein injection of KPC and KPCY clones into aged mice resulted in increased and larger metastases compared to young mice. Using imaging mass cytometry, we identified that liver metastases in aged mice were immune excluded with low CD8+ T cell infiltration and increased spatial interactions between immune cells and fibroblast populations with immunosuppressive phenotypes. Together, these data show that aging alters the primary tumor and metastatic liver microenvironments to promote more efficient metastatic spread of PDAC cells. We will present this and other ongoing work targeting the aging-driven GDF-15 signaling for the treatment and prevention of PDAC metastasis. Citation Format: Emma Kartalia, James M. Leatherman, Jae W. Lee, Sara E. Young, Elizabeth M. Jaffee, Won Jin Ho, Daniel J. Zabransk. Aged microenvironments promote liver metastasis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2551.