Phospholipase D2 Regulation of MT1‐MMP Membrane Trafficking Promotes Breast Cancer Metastasis

Abstract

Metastasis is the major cause of breast cancer death. However, despite considerable progress, the signaling events specifically driving cancer cell invasion and metastasis remain largely unknown. In this study, we show that removal of the gene encoding phospholipase D2 (PLD2), which generates the signaling lipid phosphatidic acid (PA), strongly reduced circulating tumor cells and lung metastases in the MMTV‐Neu breast cancer mouse model, whereas it had no effect on tumor initiation and growth. Consistently, migration, invasion and invadopodia, were greatly reduced in primary mouse tumor cells and human breast cancer cell lines lacking PLD2, suggesting that PLD2 promotes tumor metastasis by regulating the local invasion of tumor cells. A PA‐binding protein screening and biochemical analyses revealed that PA specifically binds to a motor protein, Kinesin‐1, and regulates its association with intracellular vesicles. Inhibition of the PLD2‐PA‐Kinesin‐1 pathway by inhibitors or PLD2 knockout blocked the plasma membrane targeting of MT1‐MMP, a matrix metalloproteinase that is required for cancer cell invasion and invadopodia formation. Taken together, these results indicate that PLD2‐generated PA promotes breast cancer metastasis by regulating membrane trafficking of proteins that are critical for cancer cell invasion, and identify that PLD2 is a potential target for treating metastatic breast cancer.