Luca Andreea C, Kurnaeva Margarita, John Daniel K, Machtinger Michael, Vollmer Nadja H J, Mödl Bernadette, Hannich J Thomas, Eckhard Margret, Lam Hon S, Musiejovsky Laszlo, Trenk Christoph, Homolya Monika, Fürnsinn Clemens, Sombke Andy, Schabbauer Gernot, Eferl Robert, Sharif Omar, Casanova Emilio, Moll Herwig P
Institute of Pharmacology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
Center for Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
Cancer Lett. 2025 Jul 28;623:217733. doi: 10.1016/j.canlet.2025.217733. Epub 2025 Apr 18.
Inflammation is a widely recognized key contributor to KRAS-driven lung adenocarcinoma (LUAD). Tumor-associated macrophages (TAM) are an integral part of the tumor microenvironment and create a supportive niche that sustains inflammation-driven tumorigenesis. In the present study, we unravel a dual role of sphingosine kinase 1 (SPHK1) in KRAS-driven LUAD. While SPHK1 promotes tumorigenesis in in vitro experimental models, it paradoxically suppresses tumorigenesis in in vivo models of KRAS-mutated LUAD. Mechanistically, tumor-intrinsic loss of SPHK1 leads to disrupted lipid homeostasis, increased inflammation and infiltration by TAM, ultimately driving tumor progression. Thus, our study suggests that clinically targeting the SPHK1/S1P axis could potentially result in increased tumor progression, possibly by rewiring the tumor microenvironment toward a more inflammatory and pro-tumorigenic state.
炎症是KRAS驱动的肺腺癌（LUAD）中一个广泛认可的关键促成因素。肿瘤相关巨噬细胞（TAM）是肿瘤微环境的一个组成部分，并创造了一个支持性的生态位，维持炎症驱动的肿瘤发生。在本研究中，我们揭示了鞘氨醇激酶1（SPHK1）在KRAS驱动的LUAD中的双重作用。虽然SPHK1在体外实验模型中促进肿瘤发生，但在KRAS突变的LUAD体内模型中却反常地抑制肿瘤发生。从机制上讲，SPHK1在肿瘤内的缺失导致脂质稳态破坏、炎症增加以及TAM浸润，最终推动肿瘤进展。因此，我们的研究表明，临床上靶向SPHK1/S1P轴可能会导致肿瘤进展加剧，可能是通过将肿瘤微环境重塑为更具炎症性和促肿瘤性的状态。
