Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions
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.
Authors
- Daniel J. Renouf (ORCID: https://orcid.org/0000-0002-7597-6089)
- Sergio Corrales-Guerrero (ORCID: https://orcid.org/0000-0002-5107-3475)
- Michael P. Lisanti (ORCID: https://orcid.org/0000-0003-2034-1382)
- Megan Halloran (ORCID: https://orcid.org/0000-0003-0596-1778)
- Duan-Liang Shyu
- Adam R. Wolfe (ORCID: https://orcid.org/0000-0002-0123-7371)
- Joanna M. Karasinska (ORCID: https://orcid.org/0000-0001-6861-4189)
- Terence M. Williams (ORCID: https://orcid.org/0000-0002-1020-0845)
- Tiantian Cui (ORCID: https://orcid.org/0000-0003-0651-7193)
- Timothy C. Thompson (ORCID: https://orcid.org/0000-0003-1424-3831)
- Ryan Robb (ORCID: https://orcid.org/0000-0001-7661-7902)
- Philippe G. Frank (ORCID: https://orcid.org/0000-0003-4857-5279)
- Nicholas Denko (ORCID: https://orcid.org/0000-0001-6875-734X)
- Amy Webb (ORCID: https://orcid.org/0000-0001-5503-7300)
- Verónica Castro-Aceituno (ORCID: https://orcid.org/0000-0002-5285-3975)
- James T. Topham (ORCID: https://orcid.org/0009-0001-6601-8807)
- Wei Chen (ORCID: https://orcid.org/0000-0002-9028-622X)
- Rebecca Packard
- Sooin Baie
- David F. Schaeffer (ORCID: https://orcid.org/0000-0002-7341-1308)
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2024-10-09
- DOI
- https://doi.org/10.17615/zdd1-a503
- Primary Topic
- Caveolin-1 and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 0.00