Adam R Wolfe
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
Authors
Tiantian Cui
Sooin Baie
Sergio Corrales-Guerrero
Amy Webb
Veronica Castro-Aceituno
Duan-Liang Shyu
Joanna M Karasinska
James T Topham
Daniel J Renouf
David F Schaeffer
Megan Halloran
Rebecca Packard
Ryan Robb
Wei Chen
Nicholas Denko
Prof Michael Lisanti M.P.Lisanti@salford.ac.uk
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.
| 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 |
| Electronic ISSN | 2375-2548 |
| 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 |
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http://creativecommons.org/licenses/by-nc/4.0/