Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.
Tumor-derived exosomes are emerging mediators of tumorigenesis. We explored the function of melanoma-derived exosomes in the formation of primary tumors and metastases in mice and human subjects. Exosomes from highly metastatic melanomas increased the metastatic behavior of primary tumors by permanently 'educating' bone marrow progenitors through the receptor tyrosine kinase MET. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites and reprogrammed bone marrow progenitors toward a pro-vasculogenic phenotype that was positive for c-Kit, the receptor tyrosine kinase Tie2 and Met. Reducing Met expression in exosomes diminished the pro-metastatic behavior of bone marrow cells. Notably, MET expression was elevated in circulating CD45(-)C-KIT(low/+)TIE2(+) bone marrow progenitors from individuals with metastatic melanoma. RAB1A, RAB5B, RAB7 and RAB27A, regulators of membrane trafficking and exosome formation, were highly expressed in melanoma cells. Rab27A RNA interference decreased exosome production, preventing bone marrow education and reducing, tumor growth and metastasis. In addition, we identified an exosome-specific melanoma signature with prognostic and therapeutic potential comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. Our data show that exosome production, transfer and education of bone marrow cells supports tumor growth and metastasis, has prognostic value and offers promise for new therapeutic directions in the metastatic process.
Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, New York, USA.
Héctor
H
Peinado
Maša
M
Alečković
Simon
S
Lavotshkin
Irina
I
Matei
Bruno
B
Costa-Silva
Gema
G
Moreno-Bueno
Marta
M
Hergueta-Redondo
Caitlin
C
Williams
Guillermo
G
García-Santos
Cyrus
C
Ghajar
Ayuko
A
Nitadori-Hoshino
Caitlin
C
Hoffman
Karen
K
Badal
Benjamin A
BA
Garcia
Margaret K
MK
Callahan
Jianda
J
Yuan
Vilma R
VR
Martins
Johan
J
Skog
Rosandra N
RN
Kaplan
Mary S
MS
Brady
Jedd D
JD
Wolchok
Paul B
PB
Chapman
Yibin
Y
Kang
Jacqueline
J
Bromberg
David
D
Lyden
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002460:Cell Line; D055354:Exosomes / Q000502:physiology*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000502:physiology; D000075745:rab27 GTP-Binding Proteins
D000075745:rab27 GTP-Binding Proteins; D019859:Proto-Oncogene Proteins c-met; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins