Abstract A023: Fibroblast STAT3 activation drives organ-specific premetastatic niche formation

Pancreatic cancer is associated with a high rate of metastasis and poor prognosis. The formation of a premetastatic niche (PMN) facilitates cancer cell spread and contributes to cancer mortality. Using murine pancreatic cancer models based on expression of oncogenic KRAS in the pancreas epithelium, we discovered that remodeling of the lung microenvironment occurs in mice bearing pancreatic precursor lesions prior to cancer formation. This early lesion premetastatic niche (EL-PMN) resembles the PMN in cancer-bearing mice, and both anticipate characteristics of overt metastasis, such as transcriptional reprogramming, activation of fibroblast STAT3 signaling and infiltration of immunosuppressive Arginase 1+ macrophages. Serum IL6 drives lung fibroblast STAT3 activation; in turn, fibroblast STAT3 activation is necessary for lung metastasis establishment. Interestingly, fibroblast reprogramming did not occur in the liver, pointing to organ-specific PMN formation. The formation of an early lesion premetastatic niche may underlie early dissemination of pancreatic cancer. Citation Format: Emily L. Lasse Opsahl, Carlos E. Espinoza, Alberto Olivei, Jude Ogechukwu. Okoye, Megan Hoffman, Faith Avritt, Ahmed M. Elhossiny, Allison C. Bischoff, Katelyn L. Donahue, Mary Poggi, Padma Kadiyala, Nandini Arya, Jiaqi Shi, Kyoung Lee, Yaqing Zhang, Eileen S. Carpenter, Julianne M. Szczepanski, Timothy L. Frankel, Marina Pasca di Magliano. Fibroblast STAT3 activation drives organ-specific premetastatic niche formation [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(18_Suppl_3): nr A023.