Abstract 74: Hypoxia-fibrosis cycle in pancreatic tumor microenvironment: Implication for diagnosis and treatment

Pancreatic cancer (PC) is difficult to treat and has the lowest five-year survival rate across the world. PC are characterized by a dense fibrotic stroma composed of abundant cancer-associated fibroblasts (CAFs) and excessive extracellular matrix (ECM), which creates a pathological barrier that impedes drug delivery to tumors, leading to suboptimal treatment efficacy and resistance to current therapeutics. Like a vicious cycle, hypoxia-fibrosis cycle consists of dynamic cancer cell-CAF interactions. Currently, most clinical therapeutics aim at tumor cells while overlooking the surrounding tumor microenvironment (TME). The TME comprises all of the physiological and biochemical elements, including, but not limited to, the ECM, CAFs, cancer-associated immune cells, and the hypoxic and acidic environment. Therefore, we aim to investigate intratumor heterogeneity of PC and figure out the tumor- and TME-driven signaling by using multi-omics analysis. The data obtained from bulk and single-cell RNA sequencing, spatial transcriptomics, and tissue microarrays show that hypoxia levels were positively correlated with tumor fibrosis. Hypoxia-fibrosis cycle modulates PC progression and pro-tumoral inflammatory microenvironment, which was associated with activation of hypoxia, KRAS, mTORC1, and inflammatory response pathways. This cycle acts as a poor prognostic indicator in patients with PC. We also established a three-dimensional cell culture model mimicking cancer cell in hypoxia-fibrosis environment to validate the impacts of hypoxia-fibrosis cycle on promoting the malignant phenotype of PC cells. A dual-modality ultrasound (US) and photoacoustic (PA) real-time imaging system is demonstrated to assess tissue oxygen saturation dynamics as well as tumor fibrosis in an orthotopic PC mouse model with/without irinotecan or nanoliposomal irinotecan treatment and highlights the potential for evaluating the efficacy of cancer therapies in preclinical settings. Our work provides useful information for enhancing the effectiveness of current therapies and may have the potential to develop new precision medicines. Citation Format: Nai-Jung Chiang, Ya-Chin Hou, Jiun-I Lai, Lun-De Liao, Yan-Shen Shan. Hypoxia-fibrosis cycle in pancreatic tumor microenvironment: Implication for diagnosis and treatment [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 74.