Monocyte Preprogramming by Tobacco Carcinogens and Fructose Intake Accelerates Lung Cancer Progression via Metabolic...

Area of Science:

• Oncology
• Metabolic pathways
• Cancer research

Background:

• Tobacco smoking is the primary cause of lung cancer (LC).
• Excessive sugar intake, particularly fructose, is an emerging risk factor for LC.
• The precise mechanisms linking high-fructose intake to LC progression are not well understood.

Purpose of the Study:

• To investigate how high-fructose consumption influences the progression of lung cancer induced by tobacco carcinogens.
• To elucidate the mechanistic role of fructose metabolism in lung cancer development and progression.

Main Methods:

• Utilized mouse models of lung cancer (Kras^G12D/+-driven and LKB1^KO).
• Administered a high-fructose diet alongside tobacco carcinogens (NNK and BaP).
• Analyzed metabolic reprogramming, macrophage recruitment and polarization, and epigenetic modifications (histone acetylation, STAT3 activation).
• Examined human LC samples for macrophage markers and clinical outcome correlations.

Main Results:

• High-fructose diet combined with tobacco carcinogens (NB) significantly accelerated lung tumor progression in mouse models.
• Restricting glucose metabolism suppressed NB-induced LC progression, indicating metabolic dependency.
• NB exposure enhanced fructose uptake via upregulated fructose transporters (e.g., GLUT8).
• Metabolic reprogramming led to epigenetic changes, promoting M2 macrophage polarization.
• Human LC samples showed enrichment of pro-metastatic M2 macrophages (IL-10+, VEGFA+), correlating with poor outcomes.

Conclusions:

• High-fructose intake drives epigenetic reprogramming of macrophages, promoting lung cancer progression.
• Pro-metastatic M2 macrophages are implicated in NB-driven lung cancer.
• Targeting fructose metabolism and M2 macrophages presents potential therapeutic strategies and prognostic biomarkers for lung cancer.