Breast Cancer-Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic...

Area of Science:

• Oncology
• Cancer Metastasis
• Tumor Microenvironment

Background:

• Metastatic cancer is a leading cause of cancer-related mortality, with the metastatic microenvironment playing a critical role in disease progression.
• Cancer-associated fibroblasts (CAFs) contribute to the formation of a pro-metastatic niche by inducing inflammation and altering the extracellular matrix (ECM).
• Understanding early changes in the metastatic niche is crucial for developing strategies to inhibit metastasis.

Purpose of the Study:

• To investigate the role of Activin A (ActA) in mediating systemic changes in the lung pre-metastatic niche during breast cancer metastasis.
• To determine the functional significance of ActA signaling in lung metastasis and its association with patient survival.

Main Methods:

• Utilized mouse models of spontaneous breast cancer pulmonary metastasis.
• Assessed fibrotic changes and fibroblast rewiring in the lung pre-metastatic niche.
• Measured Activin A (ActA) levels in primary tumors and blood.
• Investigated the effect of ActA on lung fibroblasts and collagen deposition.
• Genetically targeted ActA in breast cancer cells to evaluate its impact on metastasis and survival.
• Correlated ActA levels with clinical data from breast cancer patients.

Main Results:

• Fibrotic changes and fibroblast alterations were observed in the lung pre-metastatic niche, indicating systemic influence from the primary tumor.
• Breast tumors secreted Activin A (ActA), leading to elevated blood levels in tumor-bearing mice.
• ActA upregulated profibrotic factors in lung fibroblasts, increasing collagen deposition in the pre-metastatic niche.
• Genetic targeting of ActA in breast cancer cells significantly reduced lung metastasis and improved survival in mouse models.
• High ActA levels in human breast cancer patients correlated with lung metastatic relapse and poorer survival.

Conclusions:

• Activin A (ActA) secreted by breast cancer cells drives systemic changes in the lung microenvironment, promoting fibrosis and facilitating pulmonary metastasis.
• ActA mediates cross-talk between cancer cells and cancer-associated fibroblasts, enhancing the metastatic niche.
• ActA represents a potential therapeutic target for inhibiting breast cancer metastatic relapse and improving patient outcomes.