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.
Sci Adv. 2024 Mar;10(9):eadj3551. doi: 10.1126/sciadv.adj3551. Epub 2024 Mar 1.
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.
胰腺导管腺癌 (PDAC) 的特征是其营养摄取能力，这对肿瘤的进展至关重要。在这里，我们研究了穴样内陷介导的内吞作用 (CME) 在 PDAC 进展中的作用。对来自不同数据集的患者数据进行分析表明，高 caveolin-1 (Cav-1) 表达与较高的组织学分级、最具侵袭性的 PDAC 分子亚型以及较差的临床结果密切相关。在基因工程小鼠模型中，Cav-1 缺失显著促进了总生存期和无肿瘤生存期的延长。Cav-1 缺失的肿瘤细胞系表现出增殖明显减少，尤其是在低营养条件下。用白蛋白补充细胞可挽救 Cav-1 阳性 PDAC 细胞的生长，但在低谷氨酰胺条件下 Cav-1 缺失的 PDAC 细胞中则不能。此外，Cav-1 缺失导致明显的代谢缺陷，包括糖酵解和线粒体代谢以及下游蛋白翻译信号通路减少。这些发现强调了 Cav-1 和 CME 在为胰腺肿瘤发生提供燃料、维持肿瘤生长以及通过营养摄取促进存活方面的关键作用。
