SNX27-retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis
Priyanka Sharma1, Sameena Parveen1, Lekha V Shah1
1Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Bhopal, India.
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.
Insights
Retromer and SNX27 regulate cancer cell invasion by recycling the matrix metalloprotease MT1-MMP. SNX27 overexpression in invasive breast cancer suggests its potential role in tumor progression.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Metastatic cancer cells utilize invadopodia for extracellular matrix (ECM) degradation.
- Protease trafficking to invadopodia is crucial for ECM degradation and cancer cell invasion.
Purpose of the Study:
- To investigate the role of retromer in regulating matrix invasion activity.
- To identify the specific matrix metalloproteinases (MMPs) involved in this process and their regulation.
Main Methods:
- Utilized the MDA-MB-231 metastatic breast cancer cell line.
- Investigated the function of retromer and sorting nexin 27 (SNX27) in regulating matrix metalloproteinases (MT1-MMP and MT2-MMP).
- Employed colocalization studies, isothermal titration calorimetry (ITC), and analysis of public patient databases and xenograft models.
Main Results:
- Retromer regulates matrix invasion by recycling MT1-MMP to invadopodia.
- MT1-MMP and MT2-MMP are both associated with invadopodia but reside on distinct endosomal domains.
- SNX27 and retromer share functional similarities in matrix degradation by selectively recycling MT1-MMP.
- SNX27 directly interacts with MT1-MMP.
- SNX27 is overexpressed in invasive breast cancer and its depletion prolongs survival in mice.
Conclusions:
- Retromer and SNX27 play a significant role in regulating MT1-MMP trafficking and breast cancer cell invasion.
- SNX27's role in MT1-MMP recycling and its overexpression in invasive breast cancer highlight its potential as a therapeutic target.
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