Rôle des exosomes dans le transport de

Chaire de recherche de pneumologie expérimentale
Rôle des exosomes dans le transport de
récepteurs à tyrosine kinase et l’activation de
l’angiogenèse dans le cancer bronchique non à
petites cellules
Cornelia M. Wilson
Cornelia Wilson

The first chair at the University of Limoges in the
Faculty of Medicine was created in October 2012 (5
members)
Thomas Naves

Two axes of research:
Francois
Vincent in lung cancer
 Investigate the role of RTKs and
neurotrophins
and their role in the EGFR pathway and in the angiogenesis
process
Fabrice Lalloué
 Screen for new biomarkers in theMarie-Odile
exosomesJauberteau
of serum from
lung cancer patients
Field, J.K., Nature, 2014
Intraluminal vesicles
Multivesicular
Bodies (MVB)
Exosomes
Cell
100 nm
Proteins, mRNA
and miRNAs
Angiogenesis/
Endothelial Cell
Activation
Lysosome
Invasion/
Metastasis
Immune System
Evasion
Target cell
Proliferation
Plasma membranederived vesicles
Pro-Domain
Mature Protein
Signal peptide
cleavage
pro-neurotrophins
mature neurotrophins
NGF NT-3 BDNF NT-4
NGF NT-3 BDNF NT-4
Pro-NGF
sortilin
p75NTR
TrkA
TrkB
TrkC
p75NTR
NRH2
Vps10p domain – beta-propeller with 10 blades forming a tunnel.
25-37Å
Quistgaard et al., Nat. Struct. Mol. Bio. 2009
Wilson et al., Drug Metabolism, 2014

The multifaceted receptor, sortilin (also called neurotensin (NT)
receptor-3) plays a multitude of roles in the cell

Cell death
Sortilin expression is elevated
in human cancers (Dal Farra et
al., 2001; Giorgi et al., 2008; Truzzi et al., 2008).
Receptor/
co-receptor

Shedding of the extracellular
of sortilin into the culture
Vps10domain
domain
receptors
media from several cancer cell
lines (Hermey et al., 2006; Massa
Regulated
et al., 2013; Navarro
et al., 2002).
Protein
secretion
e.g. NT

Cell
survival
transporter
However, it is uncertain the Recycling
mechanism of sortilin release from
these cells and the consequence to the microenvironment.
ECD
}
Anti-ECD
TM
ICD
}
Anti-ICD
V5/GFP
Wilson et al., JCS, 2014
CD63
hsp90
Tsg101
CD81
flotillin
sortilin
Wilson et al., JCS, 2014
Wilson et al., JCS, 2014
Wilson et al., JCS, 2014
HUVEC
Wilson et al., JCS, 2014
Wilson et al., JCS, 2014
Wilson et al., JCS, 2014
HUVEC
Matrigel
A549
Wilson et al., JCS, 2014
Chick Embryo Chorioallantoic Membrane (CAM) Model
Opening
Day
0
3
Graft
Sacifice
10
13
Dorsal
Ventral
FaDu PLKO
FA D U
20
16
A549
14
n=1
6
4
n=1
K
pL
O
S
D562 PLKO
h
S
pLKO
8
0
t
or
Sh Sortilin
D 562
20
16
14
n=1
12
10
8
4
2
n=1
0
K
pL
O
S
h
S
t
or
A549 PLKO
A 549
20
*
n=3
T u m o u r v o lu m e (m m
3
)
18
16
14
12
10
8
A 549
*
0 .2 0
n=3
0 .1 5
0 .1 0
n=3
0 .0 5
0 .0 0
K
pL
O
S
h
S
t
or
D 562
0 .2 5
n=1
0 .2 0
0 .1 5
0 .1 0
0 .0 5
n=1
0 .0 0
K
pL
O
S
h
S
t
or
T u m o u r s u r fa c e v a s c u la r is a tio n p e r m m ²
6
T u m o u r s u r fa c e v a s c u la r is a tio n p e r m m ²
T u m o u r v o lu m e (m m
3
)
18
A549 sh Sortilin
FADU
10
2
D562 sh Sortilin
D562
12
T u m o u r s u r fa c e v a s c u la r is a tio n p e r m m ²
FaDu sh Sortilin
T u m o u r v o lu m e (m m
3
)
18
FA D U
0 .2 5
n=1
0 .2 0
0 .1 5
0 .1 0
0 .0 5
n=1
0 .0 0
K
pL
O
S
h
S
t
or
n=3
6
4
2
0
K
pL
O
S
h
S
t
or
unpublished data
unpublished data

Sortilin uses a canonical pathway for secretion and is found
in exosomes

Sortilin is a key component for exosome secretion

Exosomes contain the novel sortilin complex TES linked to
two tyrosine kinase receptors, EGFR and TrkB

The TES complex exhibits a control on endothelial cells and
angiogenesis activation through exosome transfer

The TES complex exists in the circulating exosomes from
lung cancer patients