title: 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: David H. Koch Center and.
authors: Dawn R
authors: DR
authors: Christianson
authors: University of New Mexico Cancer Center and Divisions of Molecular Medicine.
authors: Andrey S
authors: AS
authors: Dobroff
authors: David H. Koch Center and.
authors: Bettina
authors: B
authors: Proneth
authors: Departments of Genitourinary Medical Oncology and.
authors: Amado J
authors: AJ
authors: Zurita
authors: David H. Koch Center and.
authors: Ahmad
authors: A
authors: Salameh
authors: David H. Koch Center and.
authors: Eleonora
authors: E
authors: Dondossola
authors: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, and.
authors: Jun
authors: J
authors: Makino
authors: Translational Informatics, and.
authors: Cristian G
authors: CG
authors: Bologa
authors: University of New Mexico Cancer Center and Divisions of Molecular Medicine.
authors: Tracey L
authors: TL
authors: Smith
authors: University of New Mexico Cancer Center and Divisions of Molecular Medicine.
authors: Virginia J
authors: VJ
authors: Yao
authors: Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors: Tiffany L
authors: TL
authors: Calderone
authors: Conway Institute of Biomedical and Biomolecular Science, University College Dublin, Belfield, Dublin 4, Ireland; and.
authors: David J
authors: DJ
authors: O'Connell
authors: Translational Informatics, and.
authors: Tudor I
authors: TI
authors: Oprea
authors: Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Tokyo 113-0033, Japan;
authors: Kazunori
authors: K
authors: Kataoka
authors: Conway Institute of Biomedical and Biomolecular Science, University College Dublin, Belfield, Dublin 4, Ireland; and.
authors: Dolores J
authors: DJ
authors: Cahill
authors: Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors: Jeffrey E
authors: JE
authors: Gershenwald
authors: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215 richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors: Richard L
authors: RL
authors: Sidman
authors: University of New Mexico Cancer Center and Hematology and Medical Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors: Wadih
authors: W
authors: Arap
authors: University of New Mexico Cancer Center and Divisions of Molecular Medicine, richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors: Renata
authors: R
authors: Pasqualini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001706:Biopsy; D002450:Cell Communication / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000473:pathology; D006801:Humans; D008024:Ligands; D008207:Lymphatic Metastasis / Q000473:pathology*; D042601:Lymphatic Vessels / Q000473:pathology*; D008545:Melanoma / Q000473:pathology*; D008819:Mice, Nude; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015203:Reproducibility of Results; D012878:Skin Neoplasms; D016896:Treatment Outcome; D000096142:Cutaneous Malignant Melanoma
chemical_list: D008024:Ligands; C517191:PPP2R1A protein, human; D010455:Peptides; D054648:Protein Phosphatase 2
keywords: cell surface peptide; cell–cell interaction; lymphatic targeting; phage display