Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models

Area of Science:

• Cellular metabolism
• Cancer biology
• Molecular oncology

Background:

• AMP-activated protein kinase (AMPK) is a key energy sensor with context-dependent roles in cancer.
• LKB1 is the primary upstream kinase for AMPK and is frequently mutated in human non-small cell lung cancer (NSCLC).
• The function of AMPK in autochthonous genetic models of epithelial cancer remains largely unexplored.

Purpose of the Study:

• To investigate the role of AMPK in KrasG12D-driven murine non-small cell lung cancer (NSCLC).
• To determine if AMPK deletion impacts tumor growth in genetic mouse models.
• To elucidate the molecular mechanisms by which AMPK influences NSCLC progression.

Main Methods:

• Utilized autochthonous genetic mouse models with KrasG12D expression and targeted deletion of AMPK or LKB1.
• Assessed lung tumor burden and growth dynamics following genetic manipulation of AMPK.
• Investigated the regulatory role of AMPK in lysosomal gene expression via the Tfe3 transcription factor.

Main Results:

• AMPK deletion did not accelerate tumor growth in KrasG12D mice, contrasting with LKB1 deletion.
• Deletion of AMPK in KrasG12D p53(f/f) tumors significantly reduced lung tumor burden.
• AMPK was found to be essential for NSCLC growth by regulating lysosomal gene expression through Tfe3.

Conclusions:

• AMPK plays a critical role in supporting KrasG12D-driven NSCLC growth.
• The AMPK-Tfe3-lysosome axis represents an unrecognized mechanism promoting NSCLC progression.
• Targeting AMPK may offer a novel therapeutic strategy for NSCLC.