Yoshiaki Sunami

Pancreatic cancer’s substantial impact on cancer-related mortality, responsible for 8% of cancer deaths and ranking fourth in the US, persists despite advancements, with a five-year relative survival rate of only 11%. Forecasts predict a 70% surge in new cases and a 72% increase in global pancreatic cancer-related deaths by 2040. This review explores the intrinsic metabolic reprogramming of pancreatic cancer, focusing on the mevalonate pathway, including cholesterol biosynthesis, transportation, targeting strategies, and clinical studies. The mevalonate pathway, central to cellular metabolism, significantly shapes pancreatic cancer progression. Acetyl coenzyme A (Acetyl-CoA) serves a dual role in fatty acid and cholesterol biosynthesis, fueling acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) development. Enzymes, including acetoacetyl-CoA thiolase, 3-hydroxy-3methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA reductase, are key enzymes in pancreatic cancer. Inhibiting HMG-CoA reductase, e.g., by using statins, shows promise in delaying PanIN progression and impeding pancreatic cancer. Dysregulation of cholesterol modification, uptake, and transport significantly impacts tumor progression, with Sterol O-acyltransferase 1 (SOAT1) driving cholesterol ester (CE) accumulation and disrupted low-density lipoprotein receptor (LDLR) expression contributing to cancer recurrence. Apolipoprotein E (ApoE) expression in tumor stroma influences immune suppression. Clinical trials targeting cholesterol metabolism, including statins and SOAT1 inhibitors, exhibit potential anti-tumor effects, and combination therapies enhance efficacy. This review provides insights into cholesterol metabolism’s convergence with pancreatic cancer, shedding light on therapeutic avenues and ongoing clinical investigations.

Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States, and the overall 5 year survival rate is still only around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, in part due to the dense stromal tumor microenvironment, where cancer-associated fibroblasts are the major stromal cell type. Cancer-associated fibroblasts further play a key role in cancer progression, invasion, and metastasis. Cancer-associated fibroblasts communicate with tumor cells, not only through paracrine as well as paracrine-reciprocal signaling regulators but also by way of exosomes. In the current manuscript, we discuss intercellular mediators between cancer-associated fibroblasts and pancreatic cancer cells in a paracrine as well as paracrine-reciprocal manner. Further recent findings on exosomes in pancreatic cancer and metastasis are summarized.