Hypoxia-Fibrosis Cycle in Pancreatic Cancer Reveals Potential Pathways Associated with Tumor Progression and Predicts Poor Prognosis

Pancreatic cancer (PC) is difficult to treat and has the lowest five-year survival rate across the world. PC is characterized by desmoplasia 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. Tumor hypoxia develops due to the rapid and uncontrollable cell proliferation that outstrips the oxygen supply. This oxygen-starved environment forces cancer cells not only to adapt in ways that typically enhance tumor survival and growth but also to produce signaling molecules that promote the transformation of fibroblasts into CAFs. CAF-induced ECM increases tumor cell migratory and invasive capacities to support tumor dissemination. ECM protein themselves can also activate cellular signaling pathways resulting in CAF activation. 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. Our work provides useful information for enhancing the effectiveness of current therapies and may have the potential to develop new precision medicines.

YS Shan devoted in management of biliopancreatic cancer and gastric cancer, the translational study of biliary tract cancer, pancreatic cancer, gastric cancer and GIST. He performed several IITs and attended international trials in stomach, biliary, and pancreatic cancer. For his excellent achievement, he was elected to be the Dean of College of Medicine, NCKU. In 2024, He was also nominated as chief of Taiwan Surgical Society of Gastroenterology and Taiwan Gastric Cancer Society. Dr Shan has published more than 260 papers in reputed journals and got several awards for his excellent research.