Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Tumor heterogeneity is common in human cancers and linked to poor clinical outcomes.
• The mechanisms driving metastatic progression in heterogeneous tumors are not fully understood.

Purpose of the Study:

• To investigate the role of minor subclones in promoting breast cancer metastasis.
• To elucidate the mechanisms by which cooperating subclones drive metastatic outgrowth.

Main Methods:

• Expression profiling of epithelial and stromal cells from primary and metastatic lesions.
• Single-cell RNA sequencing (scRNA-seq) of CD45+ immune cells.
• In vivo experiments involving neutrophil depletion.

Main Results:

• Minor breast cancer subclones expressing IL11 and FIGF (VEGFD) cooperate to promote metastasis.
• This cooperation is indirect, mediated by microenvironmental interactions, particularly with neutrophils.
• IL11 acts on mesenchymal stromal cells to induce pro-tumorigenic neutrophils, leading to polyclonal metastases.

Conclusions:

• Minor subclones and non-cell-autonomous interactions are critical drivers of metastatic progression.
• Targeting IL11-mediated pathways and neutrophils may offer therapeutic strategies against metastasis.