SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

Abstract

A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECM degradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, we demonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity by recycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressed metalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were located on the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrix degradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromer could directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed or frequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell lines showed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumor samples.

Interplay Between SNX27 and DAG Metabolism in the Control of Trafficking and Signaling at the IS

“…Thus, it will be of great interest to investigate if these molecules also play a role in the polarization and signaling triggered in the APC. Furthermore, some findings on SNX27 and DAG dynamics during IS formation could be extrapolated to other models of polarized trafficking such as invadopodia formation or the neuronal synapse, where SNX27 is associated with numerous pathological conditions [131][132][133][134].…”

“…The importance of this complex is underscored by the fact that SNX27 deficiency or mutation is associated with synaptic dysfunction and a variety of neurological diseases such as Alzheimer's disease or Down syndrome [131,132]. Additionally, recent studies suggested that SNX27-retromer-mediated trafficking favors breast cancer metastasis [133,134]. Therefore, further research on SNX27 will shed light on immune and neuronal function and dysfunction, as well as increase the understanding of tumor invasiveness.…”

Sorting Nexin 27 as a potential target in G�protein‑coupled receptor recycling for cancer therapy (Review)

“…endosomal signal transduction before being trafficked to the cell surface (4). Interestingly, several latest research reports have indicated that SNX27 may contribute to cancer development via recycling cancer-associated proteins (5,6).…”

“…SNX27 knockdown dramatically decreased cell motility owing to increased expression of E-cadherin and β-catenin, which contributes to adhesion formation and mesenchymal-epithelial transition. Studies have further shown that SNX27 regulates matrix invasion by cancer cells by recycling matrix metalloprotease depending on its direct interaction (6,60). Additionally, SNX27 is involved in regulating energy substance uptake in cancer cells via recycling energy transport receptors.…”

“…Components internalized from the plasma membrane can be transported to the plasma membrane for rapid recycling, to lysosomes for degradation, or to endosomes for short-term storage via endosomal signal transduction before being trafficked to the cell surface ( 4 ). Interestingly, several latest research reports have indicated that SNX27 may contribute to cancer development via recycling cancer-associated proteins ( 5 , 6 ).…”