Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.

Abstract

Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.

• Authors: Dawn R Christianson, Andrey S Dobroff, Bettina Proneth, Amado J Zurita, Ahmad Salameh, Eleonora Dondossola, Jun Makino, Cristian G Bologa, Tracey L Smith, Virginia J Yao, Tiffany L Calderone, David J O'Connell, Tudor I Oprea, Kazunori Kataoka, Dolores J Cahill, Jeffrey E Gershenwald, Richard L Sidman, Wadih Arap, Renata Pasqualini
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 8 Pg. 2521-6 (Feb 24 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25659743 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ligands
• PPP2R1A protein, human
• Peptides
• Protein Phosphatase 2

Topics

• Amino Acid Sequence
• Animals
• Biopsy
• Cell Communication (immunology)
• Cell Membrane (metabolism)
• Endothelial Cells (metabolism, pathology)
• Endothelium, Lymphatic (pathology)
• Humans
• Ligands
• Lymphatic Metastasis (pathology)
• Lymphatic Vessels (pathology)
• Melanoma (pathology)
• Mice, Nude
• Molecular Mimicry
• Molecular Sequence Data
• Peptides (chemistry, immunology)
• Protein Phosphatase 2 (metabolism)
• Reproducibility of Results
• Skin Neoplasms
• Treatment Outcome
• Melanoma, Cutaneous Malignant