Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.

Wolfe, Adam R; Cui, Tiantian; Baie, Sooin; Corrales-Guerrero, Sergio; Webb, Amy; Castro-Aceituno, Veronica; Shyu, Duan-Liang; Karasinska, Joanna M; Topham, James T; Renouf, Daniel J; Schaeffer, David F; Halloran, Megan; Packard, Rebecca; Robb, Ryan; Chen, Wei; Denko, Nicholas; Lisanti, Michael

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.

Citation

Wolfe, A. R., Cui, T., Baie, S., Corrales-Guerrero, S., Webb, A., Castro-Aceituno, V., …Lisanti, M. (2024). Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions. Science Advances, 10(9), eadj3551. https://doi.org/10.1126/sciadv.adj3551

• Journal Article Type: Article
• Acceptance Date: Jan 26, 2024
• Online Publication Date: Mar 1, 2024
• Publication Date: Mar 1, 2024
• Deposit Date: Mar 18, 2024
• Publicly Available Date: Mar 18, 2024
• Journal: Science advances
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 9
• Pages: eadj3551
• DOI: https://doi.org/10.1126/sciadv.adj3551
• Keywords: Mice, Cell Line, Tumor, Carcinoma, Pancreatic Ductal - genetics - metabolism, Humans, Animals, Signal Transduction, Caveolae - metabolism - pathology, Pancreatic Neoplasms - pathology, Endocytosis