Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tumor invasion and metastasis are critical for cancer progression.
• KRAS-driven lung cancer subtypes display diverse invasion patterns affecting growth and treatment response.
• Targeting invasion-linked growth vulnerabilities remains a challenge in preclinical models.

Purpose of the Study:

• To develop an experimental system for screening targetable signaling pathways associated with early 3D invasion in KRAS-driven lung adenocarcinoma subtypes.
• To identify specific molecular mechanisms driving invasion in different KRAS-mutant lung cancer subtypes.

Main Methods:

• Utilized live-cell imaging of bronchial epithelial cells in a 3D invasion matrix.
• Performed transcriptomic profiling to identify invasion-linked gene expression changes.
• Investigated the role of LKB1, BMP6, and ALK2 signaling in lung cancer models.

Main Results:

• Identified mutant LKB1-specific upregulation of BMP6, which drives hepcidin expression and iron-regulated growth.
• Demonstrated that intact LKB1 normally restricts ALK2/BMP6-fueled growth.
• Showed potent tumor growth suppression in preclinical models by inhibiting the ALK2/BMP6 axis using clinical-stage inhibitors.
• Observed elevated BMP6 expression in human LKB1-mutant lung tumors.

Conclusions:

• LKB1 functions as a regulator of iron-mediated growth in lung cancer.
• Inhibition of the ALK2/BMP6 signaling pathway represents a promising therapeutic strategy for LKB1-mutant lung cancer.
• This finding offers a rapidly translatable therapeutic vulnerability for patients with LKB1-mutant lung cancer.