Centre de Recherche en Cancérologie de Marseille (CRCM), Unité 1068, Institut National de la Santé et de la Recherche Médicale, Marseille, France.
Institut Paoli-Calmettes (IPC), Marseille, France.
EMBO J. 2022 May 2;41(9):e110466. doi: 10.15252/embj.2021110466. Epub 2022 Mar 21.
Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.
胰腺导管腺癌 (PDA) 肿瘤细胞缺氧且缺乏营养物质，因此必须调整其代谢以确保增殖。在某些生理状态下，细胞依赖酮体来满足其代谢需求，尤其是在营养物质应激时。在这里，我们表明 PDA 细胞可以激活酮体代谢，β-羟丁酸 (βOHB) 是一种替代的细胞内或全身性燃料，可以促进 PDA 的生长和进展。PDA 细胞激活酮体生成所需的酶，利用各种营养物质作为酮体形成的碳源。通过评估小鼠自发性 PDA 肿瘤中的代谢基因表达，我们发现 HMG-CoA 裂解酶 (HMGCL)，参与酮体生成，与正常胰腺相比，在 PDA 中是最失调的代谢酶之一。体外耗尽 HMGCL 会阻碍迁移、肿瘤细胞侵袭性和无锚定肿瘤球体的紧实。此外，破坏 HMGCL 会极大地减少体内 PDA 肿瘤的生长，而 βOHB 会刺激转移到肝脏的扩散。这些发现表明 βOHB 增加了 PDA 的侵袭性，并确定 HMGCL 和酮体生成是限制 PDA 进展的代谢靶点。
