Ras drives malignancy through stem cell crosstalk with the microenvironment

Area of Science:

• Oncology
• Cancer Biology
• Molecular Signaling

Background:

• Squamous cell carcinomas develop from benign papillomas, driven by RAS-MAPK signaling.
• Cancer stem cells (CSCs) at tumor interfaces gain resistance to therapies.
• The role of CSCs in the progression from benign to invasive squamous cell carcinoma is not fully understood.

Purpose of the Study:

• To investigate the role and mechanisms of cancer stem cells in driving squamous cell carcinoma progression.
• To elucidate the dynamic signaling crosstalk between CSCs and their microenvironment during malignant transformation.

Main Methods:

• Utilized a clonal skin HRASG12V mouse model.
• Employed single-cell transcriptomics, chromatin landscaping, lentiviral reporters, and lineage tracing.
• Functionally examined key signaling pathways involved in CSC-microenvironment interactions.

Main Results:

• Oncogenic RAS activation in CSCs triggers gene expression rewiring and aberrant signaling crosstalk.
• This crosstalk activates angiogenesis, TGFβ, leptin/leptin receptor, and PI3K-AKT-mTOR signaling pathways.
• Dynamic temporal interactions between CSCs and the microenvironment are critical for malignant progression.

Conclusions:

• Aberrant, non-genetic intercellular exchanges orchestrated by CSCs fuel the transition to invasive squamous cell carcinoma.
• Understanding this dynamic crosstalk offers potential therapeutic targets for advanced cancers.
• Insights into CSC-microenvironment interactions have broad implications for cancer therapeutics.