Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin

Area of Science:

• Oncology
• Cancer Biology
• Metabolic Pathways

Background:

• Aerobic glycolysis is a hallmark of cancer, but targeting it has yielded limited clinical success.
• Squamous cell carcinoma (SCC) can arise from hair follicle stem cells (HFSCs), which rely on aerobic glycolysis.
• Lactate dehydrogenase (Ldh) is vital for HFSC activation, prompting investigation into its role in SCC.

Purpose of the Study:

• To determine if Ldh activity is critical for SCC tumorigenesis or merely a marker of its stem cell origin.
• To investigate the necessity of Ldh-mediated aerobic glycolysis in SCC development.

Main Methods:

• Genetic manipulation of Ldh activity in HFSC-driven murine SCC models.
• Assessment of tumorigenesis parameters: incidence, latency, proliferation, volume, EMT, gene expression, and immune response.
• Metabolomic analysis and FDG-PET imaging to quantify glycolytic flux and glucose uptake in Ldha-null tumors.

Main Results:

• Altering Ldh activity in HFSC-mediated tumorigenesis had no impact on tumor formation, growth, or associated molecular and immunological features.
• Ldha-null tumors exhibited significantly reduced glycolytic metabolites and decreased glucose uptake.
• Despite metabolic alterations, tumor development was not affected by Ldh abrogation.

Conclusions:

• Ldh activity and associated aerobic glycolysis are not essential for the tumorigenesis of SCC originating from HFSCs.
• Squamous cancer cells do not require heightened glycolytic activity for cancer initiation or progression.
• These findings challenge the therapeutic targeting of aerobic glycolysis in SCC.