Early-stage lung cancer is driven by a transitional cell state dependent on a KRAS-ITGA3-SRC axis

Area of Science:

• Molecular Biology
• Oncology
• Cell Biology

Background:

• Glycine-12 mutations in KRAS (KRAS^G12) are key initiators of lung adenocarcinoma (LUAD).
• KRAS^G12 mutations alter alveolar type-II progenitor (AT2) cells, but their interaction with lung homeostasis and cell fate remains unclear.

Purpose of the Study:

• To investigate the impact of KRAS^G12D mutation on AT2 cell transcriptional dynamics and lung homeostasis.
• To identify conserved regulators of AT2 cell plasticity and their role in LUAD initiation.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of AT2-mesenchyme organoid co-cultures, mouse models, and human LUAD patient samples.
• Temporal analysis of KRAS^G12D mutation effects on AT2 cell gene expression.
• Inhibition assays using KRAS^G12D and SRC inhibitors in organoid models.

Main Results:

• A transient injury/plasticity state precedes normal AT2 cell self-renewal and differentiation.
• KRAS^G12D-mutant AT2 cells exhibit persistent retention of this injury/plasticity state.
• Altered receptor expression, including ITGA3 and SRC co-expression, characterizes the KRAS^G12D-associated injury state across models.
• Combined KRAS^G12D and SRC inhibition reduced growth of KRAS^G12D-mutant AT2 organoids.

Conclusions:

• The lung repair injury/plasticity state is co-opted during AT2 cell self-renewal and LUAD initiation by KRAS mutations.
• Early-stage LUAD may be treatable by targeting the oncogenic aspects of this hijacked cell state.
• Targeting KRAS^G12D and SRC concurrently presents a potential therapeutic strategy for LUAD.