CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Tumor-associated macrophages (TAMs) are known to influence cancer progression, but the specific mechanisms driving metastasis remain incompletely understood.
• The role of chemokines, such as CCL18, in mediating the pro-metastatic functions of TAMs in breast cancer requires further elucidation.

Purpose of the Study:

• To investigate the role of CCL18 produced by TAMs in promoting breast cancer metastasis.
• To identify the receptor mediating CCL18's effects on cancer cell invasiveness and to validate its role in vivo.

Main Methods:

• Quantification of CCL18 expression in breast TAMs and correlation with patient survival data.
• In vitro assays assessing the impact of CCL18 on cancer cell invasiveness, integrin clustering, and extracellular matrix adherence.
• Identification and functional validation of the CCL18 receptor, PITPNM3, including its role in intracellular calcium signaling.
• In vivo studies using breast cancer xenografts to evaluate the effect of CCL18 and PITPNM3 on tumor metastasis.

Main Results:

• Breast TAMs were found to abundantly produce CCL18, with higher expression correlating with increased metastasis and reduced patient survival.
• CCL18 significantly enhanced breast cancer cell invasiveness by promoting integrin clustering and extracellular matrix adhesion.
• PITPNM3 was identified as the functional receptor for CCL18, mediating its pro-metastatic effects through intracellular calcium signaling.
• CCL18 administration promoted breast cancer xenograft metastasis, while suppression of PITPNM3 abrogated these pro-metastatic effects.

Conclusions:

• CCL18 secreted by TAMs is a key driver of breast cancer metastasis.
• The CCL18-PITPNM3 axis represents a novel mechanism promoting cancer cell invasion and spread.
• Targeting the CCL18-PITPNM3 pathway may offer a therapeutic strategy to inhibit breast cancer metastasis.