KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.

Area of Science:

• Oncology
• Cell Biology
• Cancer Stem Cells

Background:

• Cancers often arise from stem or progenitor cells acquiring mutations.
• Pulmonary alveolar epithelial type II (AT2) cells are a known cell of origin for lung adenocarcinoma.
• The role of differentiated cells as cancer origins is less understood.

Purpose of the Study:

• To investigate the potential of differentiated cells as a source of lung adenocarcinoma.
• To explore the reprogramming capacity of oncogenic KRAS in differentiated lung cells.
• To understand the influence of cell of origin on tumor behavior and histology.

Main Methods:

• Expression of KRAS(G12D) in differentiated AT1 cells in a mouse model.
• Analysis of cell reprogramming, tumor formation, and progression.
• Assessment of ERK and WNT pathway activation in response to oncogenic drivers.

Main Results:

• Differentiated AT1 cells can be reprogrammed into AT2 stem cells by KRAS(G12D) expression.
• These reprogrammed cells form indolent lung adenocarcinomas with lepidic features.
• WNT activation differentially affects AT1- and AT2-derived adenomas; ERK augmentation promotes AT1-derived tumor progression.

Conclusions:

• AT1 cells represent a novel cell of origin for lung adenocarcinoma, recapitulating lepidic cancer features.
• Oncogenic KRAS can reprogram differentiated cells back to a stem-like state, initiating tumorigenesis.
• The cell of origin profoundly influences cancer behavior, irrespective of driver oncogenes.