TY - JOUR
T1 - Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions
AU - Wolfe, Adam R.
AU - Cui, Tiantian
AU - Baie, Sooin
AU - Corrales-Guerrero, Sergio
AU - Webb, Amy
AU - Castro-Aceituno, Veronica
AU - Shyu, Duan Liang
AU - Karasinska, Joanna M.
AU - Topham, James T.
AU - Renouf, Daniel J.
AU - Schaeffer, David F.
AU - Halloran, Megan
AU - Packard, Rebecca
AU - Robb, Ryan
AU - Chen, Wei
AU - Denko, Nicholas
AU - Lisanti, Michael
AU - Thompson, Timothy C.
AU - Frank, Philippe
AU - Williams, Terence M.
N1 - Publisher Copyright:
© 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc).
PY - 2024/3
Y1 - 2024/3
N2 - 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.
AB - 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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U2 - 10.1126/sciadv.adj3551
DO - 10.1126/sciadv.adj3551
M3 - Article
C2 - 38427741
AN - SCOPUS:85186748224
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 9
M1 - eadj3551
ER -