2024
Sci Adv. 2024 Mar;10(9):eadj3551. doi: 10.1126/sciadv.adj3551. Epub 2024 Mar 1.
Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions
Department of Radiation Oncology, The University of Arkansas for Medical Sciences, The Winthrop P. Rockefeller Cancer Institute, Little Rock, AR, USA. Department of Radiation Oncology, City of Hope, Duarte, CA, USA. Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA. Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA. Pancreas Centre BC, Vancouver, BC, Canada. Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada. Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Department of Pathology, The Ohio State University Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA. Translational Medicine, University of Salford, Greater Manchester M5 4WT, UK. Lunella Biotech, Inc., 145 Richmond Road, Ottawa, ON K1Z 1A1, Canada. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. SGS France, Health & Nutrition, Saint-Benoît, France. N2C, Nutrition Growth and Cancer, Faculté de Médecine, Université de Tours, Inserm, UMR, 1069 Tours, France.
Service type: Knockout mice
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.
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