Transient commensal clonal interactions can drive tumor metastasis.

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment

Background:

• Functional heterogeneity and crosstalk among tumor cells are critical but poorly understood aspects of cancer progression.
• Ovarian clear cell carcinoma (OCCC) models are essential for studying metastasis, particularly the formation of ascites and peritoneal tumors.

Purpose of the Study:

• To investigate the role of functional heterogeneity and interclonal interactions in promoting metastasis of OCCC.
• To elucidate the mechanisms by which transient tumor subpopulations contribute to metastatic dissemination.

Main Methods:

• Generation of clonal OCCC populations from a patient-derived model.
• Engineering clones with Gaussia luciferase for growth monitoring and DNA barcodes for fate tracking.
• Intraperitoneal transplantation of clonal and multiclonal mixtures in mice to study tumor progression and metastasis.

Main Results:

• A single clone, CL31, robustly formed ascites but not solid tumors in clonal settings.
• Multiclonal mixtures led to extensive solid peritoneal metastases, primarily composed of CL31.
• CL31's metastatic potential in mixtures was dependent on amphiregulin secreted by non-tumorigenic clones, facilitating mesothelial clearance.

Conclusions:

• Transient, non-tumorigenic tumor subpopulations can act as commensals, promoting metastasis of other clones via a
• hit-and-run
• mechanism.
• Interactions between distinct tumor cell subpopulations play a crucial role in overcoming metastatic barriers.