Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic...

Area of Science:

• Cancer Biology
• Cellular Microenvironment
• Metastasis Research

Background:

• Metastatic colonization requires tumor cells to create a supportive microenvironment.
• The precise temporal and molecular mechanisms of this process are not fully understood.

Purpose of the Study:

• To elucidate the role of cancer cell phenotype and microenvironment interactions in metastatic colonization.
• To investigate the molecular signaling pathways involved in the establishment of a metastatic niche.

Main Methods:

• Analysis of metastatic initiating cells (MICs) and their interaction with lung fibroblasts.
• Investigating the role of Thrombospondin 2 (THBS2) and the kinase AXL.
• Assessing the impact of epithelial-to-mesenchymal transition (EMT) status on metastatic competence.
• Studying signaling pathways including TGF-β and BMP/SMAD.

Main Results:

• Metastatic initiating cells (MICs) activate lung fibroblasts through Thrombospondin 2 (THBS2) expression.
• Inhibiting the epithelial-to-mesenchymal transition (EMT) kinase AXL reduces THBS2 secretion and metastatic ability.
• Disseminated cells revert to an epithelial phenotype, favoring BMP/SMAD1-5 over TGF-β/SMAD2-3 signaling for proliferation.
• Activated fibroblasts promote this phenotypic transition in cancer cells.

Conclusions:

• Cancer cell epithelial-to-mesenchymal transition (EMT) status and microenvironment activation are dynamically linked during metastasis.
• A crosstalk exists where EMT initially triggers niche activation, which then regulates the EMT status for colonization and proliferation.