Upload
others
View
4
Download
0
Embed Size (px)
Citation preview
β
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
β
Agtr1a-/-
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
ob/ob
Ptf1-Cre/ KrasLSL-G12D/+ / p53LSL-R172H/+ Ptf1-Cre / ROSA26-LSL-
rtTa-IRES-eGFP / TetO-KrasTetO-LSL-G12D / p53L/+
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
α
α
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
Col1a2, Tgfß1 and matrix metalloproteinases
Agtr1a-/-)
α
α
α
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
vs
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
AT2-/-
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
in vitro
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
γ
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
e.g
ob/ob), (agtr1a agtr2
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
ob/ob
SMAD4-m174
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
ob/ob
ob/ob
ob/ob
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
μ
μ
α
α
α
α
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
μ
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
μ
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Agtr1a-/-
p
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
p
μ
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
μ
μ
μ
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
***
C57/B6FVBKPC
iKRASob
/ob
20
30
40
50
Body
wei
ght (
gram
s)
Low-fat dietHigh-fat diet
** *
10 weeks of low or
high-fat diet
7 weeks of
standard chow
low or high-fat diet until tumorcollection
PAN02
(diet-
induc
ed
obes
ity) AK4.4
0.0
0.5
1.0
1.5
2.0
Tum
or w
eigh
t (gr
ams) *
***
Figure 1
Lean ObeseMesenteriesC iBA
LeanObese
Standard chow
Lean
Obese
0
5
10
15
Num
ber o
f mes
ente
ric
met
asta
ses
*
Lean
Obese
Lean
Obese
0.0
0.5
1.0
1.5
2.0
2.5
Num
ber o
f wal
l m
etas
tasi
s *
*
PAN02 AK4.4PAN02ii iii
PAN02
(ge
netic
ally-i
nduc
ed
obes
ity)
Research. on June 8, 2020. ©
2016 Am
erican Association for C
ancercancerdiscovery.aacrjournals.org
Dow
nloaded from
Author m
anuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author M
anuscript Published O
nlineFirst on M
ay 31, 2016; DO
I: 10.1158/2159-8290.CD
-15-1177
PAN02AK4.4
0
5
10
20
30
Tum
or a
dipo
cyte
s / 1
0mm *
**
2
Masson’s Trichome
Figure 2
PAN02AK4.4
0
20
40
60
80
100
Tum
or a
dipo
cyte
dia
met
er (u
m)
***
i ii
iiiii
Lean
Obe
seiiiAdipose tissue PAN02 tumor A
PAN02 AK4.4 AK4.4
Pancreas
Tumor
Adipocytes
iv
Adipocytes
Masson’s Trichome
Number Diameter
C
PAN02 AK4.4 KPCii
Obe
seLe
an
Collagen IDAPI
PAN02 AK4.4
Obe
seLe
an
iFibrillar
collagen(SHG)
Col
lage
n I (
IF)
(Nor
mal
ized
to L
ean)
PAN02AK4.4 KPC
0.00.51.01.52.02.5
* *
iv
Lean ObeseB
Masson’s Trichome
iii
PAN02i DAPI
Obe
seLe
an
KPC
Fibr
illar c
olla
gen
(SH
G)
(Nor
mal
ized
to L
ean)
PAN02AK4.4
0
1
2
3
4
**
PAN02KPC
AK4.40
1
2
3
SMA
(n
orm
aliz
ed to
lean
) *
PAN02KPC
AK4.40
1
2
3
4
SMA+
/Col
I+
(nor
mal
ized
to le
an)
**
Masson’s Trichome
Pancreatic Stellate Cells
Collagen I-producingPancreatic Stellate Cells
Lean ObeseLean Obese
Lean Obese Lean Obese
AdipocytesAdipocytes
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Tum
or w
eigh
t (gr
ams)
Lean
Lean
5FU
Obese
Obese
5FU
0.0
0.2
0.4
0.6
0.8
1.0
*
Lean
Lean
5FU
Obese
Obese
5FU
0.0
0.2
0.4
0.6
0.8
1.0
Tum
or w
eigh
t (gr
ams)
*
CA-IXHif-1 CA-IX
Hif-10
1
2
3
Fold
cha
nge
com
pare
d to
lean
(nor
mal
ized
to
-act
in)
PAN02 AK4.4
0.06Lean Obese
% o
f ves
sel a
rea
/ tum
or
Vesse
ls
(CD31
+)
Perfus
ed
vess
els
(CD31
+/lec
tin+)
0
5
10
15
*
Figure 3A
Lean Obese
B
Lean
Obese
0
1
2
3
4
% o
f injec
ted
dose
/ g
tissu
e
**
5-FU delivery
i
iiCD31 Lectin DAPI
CA-IXHif-1
Lean ObeseAK4.4
PAN02
CA-IXHif-1
C
Lean Obese
% o
f ves
sel a
rea
/ tum
or
Vesse
ls
(CD31
+)0
5
10
15
*
Perfus
ed
vess
els
(CD31
+/lec
tin+)
AK4.4PAN02
Whole tumor extractsTumor tissue (ROIs)i
ii
Lean Obese
D
Lean Obese
iii
i AK4.4PAN02 ii
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Lean
Lean
Los
Obe
se
Obe
se L
os0
10
20
30
40
% C
ol-1 / tum
or
*
Lean
Lean
Los
Obe
se
Obe
se L
os0
20
40
60
80
% C
ol-1 / tum
or
2.5Lean
Lean
Los
Obese
Obese
Los
AT1
TGFß
Sm
ad-2
vim
entin
E-c
ad
Sna
il
MM
P9
p-p3
8
p-JN
K
p-4E
BP1
p-NFkB
0.0
0.5
1.0
1.5
2.0
Pro
tein
expre
ssio
n
(norm
aliz
ed to tubulin
)
* *
*****
PAN02 AK4.4
Tum
or
weig
ht (g
ram
s)
Con
trol
Los
5FU
5FU L
os
Con
trol
Los
5FU
5FU lo
s0.0
0.2
0.4
0.6
0.8
1.0
*
Lean Obese
*
***
***
Lean
Lean
Los
Obe
se
Obe
se L
os0
2 104
4 104
6 104
Pix
el C
ount
**
Con
trol
Los
AT1KO
AT2K
O 5
FU
5FU
+Los
5FU
+AT1K
O
5FU
+AT1K
O+L
os
5FU
+AT2K
O
Con
trol
Los
AT1K
O
AT2KO5F
U
5FU+L
os
5FU
+AT1K
O
5FU
+Los
+AT1K
O
5FU
+AT2K
O
0.0
0.3
0.6
0.9
1.2
Tum
or
weig
ht (g
ram
s)
**
*
***
Lean Obese
* **
*****
Figure 4
PAN02
p-p38
T-p38
Lean Obese
PAN02
p-ERK
T-ERK
p-AKT
T-AKT
p-S6
p-4EBP1
β-actin
AK4.4Lean Obese
B
CLean Obese Obese Los
Lean
Lean
Los
Obe
se
Obe
se L
os0.0
0.5
1.0
1.5
Pro
tein
expre
ssio
n (
norm
aliz
ed to tubulin
)
**
Lean LosObeseLos
AT1
TGFβ
Smad-2
Vimentin
E-cadherin
Snail
MMP9
p-p38
t-p38
p-JNK
p-4EBP1
t-4EBP1
p-NFKB
Tubulin
E
E
D
De
sm
op
lasia
AT
1 s
ign
alin
g
ii
i
iii iv
ii
Collagen I
DAPI
Fibrillar collagen
(SHG)
SHG
Collagen I
LeanLean
Los ObeseObese
LosαSMA
Tubulin
PAN02F i ii
Lean Obese
APAN02
AK4.4
Col1a
2
MM
P2
MM
P9
Mm
p13
MM
P14
Tgfb2
Thbs2Tnf
-α
Tgfbr
1M
dk
Fgfr3
Sna
i1
Sta
t6
Tim
p30
1
2
3
4
mR
NA
Fold
Change
a-SM
A
Angio
tens
inog
en
Col
1a2
Col
3a1
Col
4a3
Dec
orin
Mm
p1a
Mm
p2
Mm
p3
Mm
p19
Timp3
Timp4Tbx
1
Bmp7
Anpep
Lysil o
xida
se0
4
8
12
mR
NA
Fold
Change
ii
i
vCollagen I
AK4.4 PAN02i
ii
Lean Obese
p-p3
8
p-ERK
p-AKT p-
s6
p-4E
BP1
p-p3
8
p-ERK
p-AKT p-
s6
p-4E
BP1
0.0
0.5
1.0
1.5
2.0
2.5
Pro
tein
expre
ssio
n (
norm
aliz
ed to
-actin)
Lean Obese
*
* 0.076
*
*
* *
iii
Lean Obese Obese Los
Tumor tissue (ROIs)
Tumor tissue (whole tumors)
Whole tumor extracts
Note: not all significant differences
are depicted for simplicity
AK4.4
EM
T
** * *
*
* *
***
i
D (cont.)
AK4.4
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
CD
31+
Lect
in+
Dou
ble
+
0
5
10
15
20
% o
f ve
ssel a
rea / tum
or *
**
B
Figure 5
Tum
or
weig
ht (g
ram
s)
Lean
Obe
se
0.0
0.5
1.0**
Obe
se
TAN
-D d
1*
AK4.4
F
CD
45+
CD
11b+
CD
11b+
Gr1
+F4/
80-
0
20
40
60
80%
im
mune c
ell
/to
tal via
ble
cells
Lean
Obese*
***
***
CD
11b+
Gr1
+F4/
80-
0
10
20
30
40
50
Imm
une c
ell
/%
of C
D45+
cells
Lean
Obese
**
PAN02A
Tum
or
weig
ht(g
ram
s)
Lean
Obe
seO
bese
TAN
-D d
1O
bese
TA
N-D
d7
0.0
0.5
1.0 ** *
i ii i ii
Lean
Obe
se
Obe
se T
AN
-D
0
5
10
15
20
25 ** **
% α
SM
A+
Col-1+
/ tum
orii
ObeseObese
TAN-DαSMA
AT1
MMP9
Col I
GAPDH
E
Lean Obese Obese TAN-D
Di
Ly6g αSMA DAPI
Col-I αSMA DAPI
C
SM
A
AT1
MM
P9
Col
I
0
1
2
3
4
5
Pro
tein
expre
ssio
n (
norm
aliz
ed to G
AP
DH
)
* *
Obese
Obese
TAN-D
ii
i
Tumor tissue (whole tumor)
Tumor tissue (whole tumors)
Whole tumor extracts
PAN02
D
Research. on June 8, 2020. ©
2016 Am
erican Association for C
ancercancerdiscovery.aacrjournals.org
Dow
nloaded from
Author m
anuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Author M
anuscript Published O
nlineFirst on M
ay 31, 2016; DO
I: 10.1158/2159-8290.CD
-15-1177
IL-1ß
+
SMA +
IL-1ß
SMA
Double
+
IL-1
ß that
is ori
ginate
d in
PSCs (% of
total
IL1ß
)
0
20
40
60
80
% o
f sta
inni
ng /
tum
or a
rea
Adipocyte-poorAdipocyte-rich
***
**
**
0.067
E
Adipocytes
PSCs
Adipocytes
IFN-yIL-
10
IL-12
IL-
6
CXCL1TNF-
0.0
0.5
1.0
1.5
5
10
15
50
100
150
Prot
ein
conc
entra
tion
(pg/
mg
of ti
ssue
pro
tein
)
Lean Obese
*
Lean
Obese
Obese
TAN-D
0
10
20
30
40
50
Tum
mor
IL-1
(pg/
mg
tissu
e pr
otei
n) * *
A
Merge DAPI
BAdipocytes
F
Figure 6
Merge DAPI
E
Tum
or w
eight
(gra
ms)
0.0
0.5
1.0
1.5
2.0
2.5 ** *
Lean
Obese
Ci Lean Obese
TAN
CD8 CD8
Treg
Lean AT1-KO
CD8
Obese AT1-KOTAN TAN TAN
CD8
Treg Treg Treg
i ii
CD
25C
D8
LY6G
CD11b
CD4
CD11b
CD11b+
/Ly6G
+CD8+
CD4+0
1
2
10
20
30
% o
f im
mun
e ce
ll / t
otal
via
ble
cells
LeanObese
**
* *
Lean AT1-KO Obese AT1-KO
*
Obese IL-1 inh. *
*
CD4+/CD25
+0
20
40
60
% o
f Tre
gs /
tota
l CD
4 ce
lls
**
CD8
TAN
Treg
Obese IL-1 inh.
ii Tumor tissue (ROI)
Tumor tissue (ROIs)Adipocytes
Adip
ocyt
e-ric
hAd
ipoc
yte-
poor
G
AdAAdAdAdAdAAdAdAddddddddippocococococytesesessssss
Merge DAPISMA
Ly6G
D
SMA IL-1
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Collag
en I
Hyalur
onan
0
10
20
30
40
50
% o
f tum
or a
rea
BMI<25 BMI>30
**
Figure 7A
BMI>30BMI<25 PDAC patient samples
B
iii
i iiBMI>30 BMI<25
Adipocytes
Col
lage
n I
Hya
luro
nan
PDAC patient samples
blood vessel
PDAC IN THE OBESE HOSTPDAC IN THE LEAN HOST
TAN
TAN recruitment
PSC activation
PSC
Tumor growth and reduced response to chemotherapy
Inflammation/immunosupression
TregCD8
CAA
Fibrosis
IL-1ßIL-1ß
TAN recruitment
IL-1ß
CAA Cancer-associated adipocyte TAN Tumor-associated neutrophil PSC Pancreatic stellate cell
Strategies to disrupt obesity-
cancer connection
IL-1ß inhibition
TAN depletion
AT1 inhibitionIL-1ß
Tumor cell proliferation
FibrosisPSCsTAN / IL-1ß
Perfusionblood vessel
Fatty stroma
Impact of obesity on chemotherapy
C
D
BMI<25
BMI>30
0
50
100
150
Adip
ocyt
e di
amet
er (u
m)
*
Masson’s Trichome
DAPI
Cum
ulat
ive
surv
ival
Cum
ulat
ive
surv
ival
i
ii
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177
Published OnlineFirst May 31, 2016.Cancer Discov Joao Incio, Hao Liu, Priya Suboj, et al. pancreatic cancer progression and resistance to chemotherapyObesity-induced inflammation and desmoplasia promote
Updated version
10.1158/2159-8290.CD-15-1177doi:
Access the most recent version of this article at:
Material
Supplementary
http://cancerdiscovery.aacrjournals.org/content/suppl/2016/06/01/2159-8290.CD-15-1177.DC1
Access the most recent supplemental material at:
Manuscript
Authoredited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been
E-mail alerts related to this article or journal.Sign up to receive free email-alerts
Subscriptions
Reprints and
To order reprints of this article or to subscribe to the journal, contact the AACR Publications
Permissions
Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)
.http://cancerdiscovery.aacrjournals.org/content/early/2016/05/28/2159-8290.CD-15-1177To request permission to re-use all or part of this article, use this link
Research. on June 8, 2020. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 31, 2016; DOI: 10.1158/2159-8290.CD-15-1177