Periostin+ Stromal Cells Guide Lymphovascular Invasion by Cancer Cells

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment

Background:

• Cancer cell dissemination to lymph nodes, especially in breast cancer, correlates with poor patient prognosis.
• Cancer-associated fibroblasts (CAFs) play a crucial role in cancer progression and metastasis.
• Periostin, a matricellular protein, can distinguish CAF subtypes and is linked to increased desmoplasia and recurrence, but its specific role in situ is unclear.

Purpose of the Study:

• To genetically trace and functionally characterize periostin-expressing CAFs in vivo during tumor growth and metastasis.
• To elucidate the specific contribution of periostin+ CAFs to cancer cell dissemination and lymph node metastasis.

Main Methods:

• In vivo genetic labeling and ablation techniques were employed to track and manipulate periostin-expressing cells.
• Spatial distribution and activation of periostin+ CAFs were analyzed in relation to tumor cells and lymphatic vasculature.
• Functional assays assessed the impact of periostin+ CAF depletion on tumor growth, collagen organization, and metastasis.

Main Results:

• Periostin-expressing CAFs were localized at periductal, perivascular margins, and enriched near lymphatic vessels.
• Highly metastatic cancer cells differentially activated periostin+ CAFs compared to poorly metastatic cells.
• Depletion of periostin+ CAFs impaired intratumoral collagen organization and significantly inhibited lymphatic metastasis, but not lung metastasis.
• Periostin ablation in CAFs reduced their ability to deposit aligned collagen and hindered cancer cell invasion through collagen and lymphatic endothelial cells.

Conclusions:

• Highly metastatic breast cancer cells activate periostin-expressing CAFs to remodel the extracellular matrix.
• These activated CAFs promote collective cancer cell invasion into lymphatic vessels, facilitating metastasis to sentinel lymph nodes.
• Targeting periostin+ CAFs may represent a therapeutic strategy to inhibit lymph node metastasis in breast cancer.