Seo Ramin, de Guzman Arvie Camille V, Park Sunghyouk, Lee Ji Youn, Kang Suk-Jo
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul, 08826, Republic of Korea.
Cell Death Differ. 2025 Mar 7. doi: 10.1038/s41418-025-01466-y.
Pancreatic ductal adenocarcinoma is characterized by a three-dimensional (3D) tumor microenvironment devoid of oxygen and nutrients but enriched in extracellular matrix, which acts as a physical and chemical barrier. In 3D, cancer cells reprogram their metabolic pathways in ways that help them survive hostile conditions. However, little is known about the metabolic phenotypes of cancer cells in 3D and the intrinsic cues that modulate them. We found that Cxcl5 deletion restricted pancreatic tumor growth in a 3D spheroid-in-Matrigel culture system without affecting cancer cell growth in 2D culture. Cxcl5 deletion impaired 3D-specific global metabolic reprogramming, resistance to hypoxia-induced cell death, and upregulation of Hif1α and Myc. Overexpression of Hif1α and Myc, however, effectively restored 3D culture-induced metabolic reconfiguration, growth, redox homeostasis, and mitochondrial function in Cxcl5 cells, reducing ferroptosis. We also found that pancreatic cancer patients with higher expression of hypoxia and metabolism-related genes whose expression is well-correlated with CXCL5 generally have poorer prognosis. Together, our findings identify an unanticipated role of Cxcl5 in orchestrating the cancer metabolic reprogramming in 3D culture that is required for energy and biomass maintenance and that restricts oxidative cell death. Thus, our results provide a rationale for targeting CXCL5 as a promising therapeutic strategy.
胰腺导管腺癌的特征是三维（3D）肿瘤微环境，其中缺乏氧气和营养物质，但富含细胞外基质，细胞外基质起到物理和化学屏障的作用。在三维环境中，癌细胞以有助于它们在恶劣条件下存活的方式重新编程其代谢途径。然而，对于三维环境中癌细胞的代谢表型以及调节它们的内在线索知之甚少。我们发现，在基质胶中培养的3D球体培养系统中，Cxcl5缺失会限制胰腺肿瘤生长，而不影响二维培养中的癌细胞生长。Cxcl5缺失会损害3D特异性的全局代谢重编程、对缺氧诱导的细胞死亡的抗性以及Hif1α和Myc的上调。然而，Hif1α和Myc的过表达有效地恢复了Cxcl5细胞中3D培养诱导的代谢重配置、生长、氧化还原稳态和线粒体功能，减少了铁死亡。我们还发现，缺氧和代谢相关基因表达较高且与CXCL5表达高度相关的胰腺癌患者通常预后较差。总之，我们的研究结果确定了Cxcl5在协调3D培养中的癌症代谢重编程方面的意外作用，这种重编程是维持能量和生物量所必需的，并且限制了氧化性细胞死亡。因此，我们的结果为将CXCL5作为一种有前景的治疗策略提供了理论依据。
