A carregar...
Publicação
Subtherapeutic Dose of Ionizing Radiation Reprograms the Pre-Metastatic Lung Niche, Accelerating Its Formation and Promoting Metastasis
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 2.4 MB | Adobe PDF |
Orientador(es)
Resumo(s)
Pre-metastatic niche (PMN) formation is a critical step in metastatic progression. However, the biological effects of subtherapeutic doses of ionizing radiation (SDIRs) following radiotherapy on this process remain unclear. Using a 4T1 breast cancer mouse model, we investigated the effects of SDIRs (3 × 0.3 Gy) on lung PMN development and metastasis upon SDIR exposure on days 8–10 post-tumor injection, followed by mastectomy and analyzed on day 24. SDIRs significantly increased the total metastatic volume (TMV) in lungs, suggesting an accelerated PMN formation. Mechanistically, the SDIR acted as an early catalyst for niche priming, upregulating Bv8 expression, enhancing neutrophil recruitment, and increasing MMP9, S100A8, and Il6 production in the PMN by day 11. Moreover, SDIR drives metastasis through distinct mechanisms. Proteomic analysis revealed SDIR-driven metabolic reprogramming, with a shift away from fatty acid metabolism toward glycolysis and lipid accumulation within the PMN. This shift contributes to extracellular matrix (ECM) remodeling, immune modulation, and the upregulation of adhesion-related pathways, shaping a microenvironment that accelerates metastatic outgrowth. By reprogramming the pre-metastatic lung, the SDIR highlights the need to integrate organ-specific radiation exposure into metastasis models. Metabolic and immune-stromal pathways emerge as potential therapeutic targets, underscoring the importance of refining radiotherapy strategies to mitigate unintended pro-metastatic effects.
Descrição
Funding Information: We thank the Radiotherapy Service, ULSSM, Lisbon, Portugal, particularly C. Raimundo, P. Aresta, P. Ribeiro, A. Maduro, J. Pereira, M. Pereira, A. Castro, C. Isidoro, and R. Pinto for their help in irradiation delivery, and R. Ferreira for treatment planning and dosimetry. I.S.V. holds a research position funded by FCT under the program contract CEEC-INST/00106/2021. J.C.G. is supported by the European Union Horizon 2020 research and innovation program (ERA project number, 952377\u2014iSTARS). Anti-Bv8 was kindly provided by Genentech Inc (South San Francisco, CA, USA). Funding Information: P.O.: under a junior researcher contract through project PTDC/MED-OUT/31118/2017 funded by Funda\u00E7\u00E3o para a Ci\u00EAncia e Tecnologia (FCT). I.S.V. holds a research position funded by FCT under the program contract CEEC-INST/00106/2021. This research was supported by FCT\u2014UID/00306/2025. Publisher Copyright: © 2025 by the authors.
Palavras-chave
metastasis pre-metastatic niche subtherapeutic dose of ionizing radiation Catalysis Molecular Biology Spectroscopy Computer Science Applications Physical and Theoretical Chemistry Organic Chemistry Inorganic Chemistry SDG 3 - Good Health and Well-being