Efficient extravasation of tumor-repopulating cells depends on cell deformability

Area of Science:

• Oncology
• Developmental Biology
• Cell Biology

Background:

• Cancer metastasis remains a major challenge, with few cells initiating secondary tumors.
• Tumor-repopulating cells (TRCs) are a highly tumorigenic subpopulation identified in 3D cultures.
• Understanding the mechanisms of metastasis initiation is crucial for developing effective therapies.

Purpose of the Study:

• To investigate the role of tumor cell properties in metastasis using a zebrafish embryo model.
• To determine the factors influencing the metastatic efficiency of TRCs compared to control cells.
• To elucidate the molecular mechanisms underlying TRC extravasation and colonization.

Main Methods:

• Injection of mouse melanoma TRCs and control cells into zebrafish embryos (Tg (fli1:EGFP or kdrl:mCherry)).
• 3D confocal microscopy to visualize TRC behavior at secondary sites.
• Gene silencing (Sox2) and manipulation of cell signaling molecules (Cdc42) to assess their impact on metastasis.
• In vitro transmigration assays to evaluate cell deformability.

Main Results:

• TRCs exhibited significantly higher efficiency in survival, growth, micrometastasis, and metastatic colonization in zebrafish embryos compared to control cells.
• TRC metastasis was dependent on Sox2; silencing Sox2 inhibited metastasis.
• High-resolution imaging revealed more efficient extravasation and micrometastasis formation by TRCs.
• TRC deformability, linked to low Cdc42 and high Sox2, was critical for efficient in vivo extravasation and in vitro transmigration.

Conclusions:

• Tumor cell deformability is a critical determinant of extravasation dynamics and metastatic potential.
• Sox2 plays a crucial role in promoting TRC metastasis, potentially by regulating cell deformability.
• Targeting cell deformability could offer novel strategies to inhibit cancer metastasis.