Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

Area of Science:

• Oncology
• Stem Cell Biology
• Molecular Biology

Background:

• Squamous cell carcinomas (SCCs) arise from stratified epithelia, with a subset metastasizing.
• The role of epithelial stem cells in SCC oncogenesis, multipotency, and metastasis remains unclear.
• Driver mutations in SCCs often target epithelial stem cells.

Purpose of the Study:

• To investigate whether epithelial stem cells contribute to oncogenic multipotency and metastasis in SCC.
• To model SCC using specific genetic mutations in mouse stem cells.
• To identify molecular mechanisms regulating SCC metastasis.

Main Methods:

• Developed a mouse model of SCC by targeting Kras(G12D) activation and Smad4 deletion in keratin 15-expressing (K15+) stem cells.
• Analyzed tumor development, cancer stem cell (CSC) populations (side population, SP), epithelial-mesenchymal transition (EMT), and metastasis.
• Investigated the role of microRNA-9 (miR-9) in metastasis and identified its targets, including α-catenin.

Main Results:

• Transgenic mice developed multilineage tumors, including metastatic SCCs.
• Increased SP cells in CSC-enriched populations correlated with EMT and lung metastasis.
• miR-9 promoted SP expansion and metastasis; inhibition reduced these effects. Increased miR-9 and α-catenin loss were observed in metastatic human SCCs.

Conclusions:

• Mutated epithelial stem cells can generate multipotent, metastatic SCCs.
• miR-9 is a key regulator of metastatic CSC expansion and SCC metastasis, targeting α-catenin.
• Tumor initiation and metastatic potential in CSCs can be distinct processes regulated by miR-9.