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

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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Publication Details

Journal
Cancer Letters
Published
2025-04-18
DOI
https://doi.org/10.1016/j.canlet.2025.217733
Citations
3
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
2.42
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Loss of SPHK1 fuels inflammation to drive KRAS-mutated lung adenocarcinoma

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Cancer Letters
RNA modifications and cancer
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Loss of SPHK1 fuels inflammation to drive KRAS-mutated lung adenocarcinoma

Margret Eckhard, Andy Sombke, Bernadette Mödl, Omar Sharif, L. Musiejovsky, Christoph Trenk, Michael Machtinger, Gernot Schabbauer, Andreea Corina Luca, Emilio Casanova, Clemens Fürnsinn, Robert Eferl, Nadja H J Vollmer, Monika Homolya, Herwig P. Moll, J. Thomas Hannich, Margarita Kurnaeva, Daniel John, Hon Shing Lam
article en
3 citations

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.

Cancer LettersVol. 623
Austrian Academy of Sciences (AT), Comprehensive Cancer Center Vienna (AT), Christian Doppler Laboratory for Thermoelectricity (AT), CeMM Research Center for Molecular Medicine (AT), Medical University of Vienna (AT)
Affordable and clean energy
Openalex Percentile: Top 12%
RNA modifications and cancer
2.42
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