Abstract A063: The role of JAK/STAT3 signaling in lung premetastatic niche formation and progression

Abstract Pancreatic ductal adenocarcinoma (PDA) is a highly deadly disease with a five-year survival rate of only 13%. Oncogenic KRAS (Kras) is a near-universal driver of PDA, and its activity is required for the formation of PDA precursor lesions, pancreatic intraepithelial neoplasia (PanIN). PanIN formation is accompanied by fibrosis and immune cell infiltration, creating a precursor tumor microenvironment that is maintained and evolves through disease progression. Our previous work has demonstrated that Kras in epithelial cells drives fibroblast activation during very early stages of pancreatic tumorigenesis and that fibroblast reprogramming occurs in a JAK/STAT3 signaling-dependent manner. Other groups have described that pancreatic cancer cells secrete specific factors to prime the liver and lung through immunomodulation and extracellular matrix remodeling, forming the premetastatic niche (PMN). Additionally, recent papers in the field have suggested a role for JAK/STAT3-reprogramming in the formation of the PMN during pancreatic tumorigenesis. Presently, it remains to be elucidated at what stage of PDA tumorigenesis the PMN is initiated, as well as the mechanisms underlying formation. In a pilot experiment, we induced pancreas specific Kras until mice had PanIN lesions but no overt malignancy. We then harvest the pancreas and lung for single cell RNA sequencing. Here, results showed that when Kras is expressed within the pancreas of a mouse, fibroblasts are reprogrammed within the lung, prior to pancreatic tumor formation. Additionally, data indicates JAK/STAT3 signaling activation present within these fibroblasts. We also used multiple lung metastasis models, both spontaneous and tail vein injection, to show persistence of this reprogramming. This suggests that pancreatic Kras expression can systemically reprogram fibroblasts to form a PMN more capable of seeding cancer cells. Our in vitro studies have showed similar results as lung fibroblasts treated with Kras ON conditioned media show increased pSTAT3. Furthermore, using multiplex ELISA on iKras conditioned media, we have identified multiple promising secreted factor hits that may play a role in lung fibroblast reprogramming. Ongoing studies aim to define the mechanism of pulmonary fibroblast reprogramming in the context of the PMN and to assess the role of pSTAT3+ fibroblast reprogramming on establishment of pulmonary metastases. Citation Format: Emily Lasse Opsahl, Carlos E Espinoza, Katelyn L Donahue, Ahmed M Elhossiny, Padma Kadiyala, Allison C Bischoff, Mary Poggi, Yaqing Zhang, Jiaqi Shi, Timothy Frankel, Marina Pasca di Magliano. The role of JAK/STAT3 signaling in lung premetastatic niche formation and progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A063.