Loss of SPHK1 fuels inflammation to drive KRAS-mutated lung adenocarcinoma

IF 9.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-04-18 DOI:10.1016/j.canlet.2025.217733

Andreea C. Luca , Margarita Kurnaeva , Daniel K. John , Michael Machtinger , Nadja H.J. Vollmer , Bernadette Mödl , J. Thomas Hannich , Margret Eckhard , Hon S. Lam , Laszlo Musiejovsky , Christoph Trenk , Monika Homolya , Clemens Fürnsinn , Andy Sombke , Gernot Schabbauer , Robert Eferl , Omar Sharif , Emilio Casanova , Herwig P. Moll

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引用次数: 0

Abstract

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.

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SPHK1的缺失会引发炎症，从而驱动kras突变的肺腺癌

炎症是公认的 KRAS 驱动的肺腺癌（LUAD）的关键诱因。肿瘤相关巨噬细胞（TAM）是肿瘤微环境中不可或缺的一部分，它创造了一个支持性生态位，维持着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。在体外实验模型中，SPHK1 促进肿瘤发生，而在 KRAS 突变的 LUAD 体内模型中，它却矛盾地抑制肿瘤发生。从机理上讲，肿瘤内源性 SPHK1 的缺失会导致脂质平衡紊乱、炎症加剧和 TAM 的浸润，最终推动肿瘤进展。因此，我们的研究表明，临床上以 SPHK1/S1P 轴为靶点可能会导致肿瘤进展加剧，这可能是通过重构肿瘤微环境，使其趋向于更具炎症性和更有利于肿瘤生成的状态。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.