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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

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β

Agtr1a-/-




ob/ob

Ptf1-Cre/ KrasLSL-G12D/+ / p53LSL-R172H/+ Ptf1-Cre / ROSA26-LSL-

rtTa-IRES-eGFP / TetO-KrasTetO-LSL-G12D / p53L/+




α

α

α

α




α




α

Col1a2, Tgfß1 and matrix metalloproteinases

Agtr1a-/-)

α

α

α

α




vs




AT2-/-




α

α




α




in vitro




γ




e.g

ob/ob), (agtr1a agtr2




ob/ob

SMAD4-m174




ob/ob

ob/ob

ob/ob




μ

μ

α

α

α

α




μ




Agtr1a-/-

p




p

μ




μ

μ

μ




***

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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

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or w

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t (gr

ams) *

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Figure 1

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10

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ber o

f mes

ente

ric

met

asta

ses

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ber o

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PAN02 AK4.4PAN02ii iii

PAN02

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netic

ally-i

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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

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PAN02AK4.4

0

20

40

60

80

100

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er (u

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i ii

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an

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seLe

an

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mal

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orm

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0.2

0.4

0.6

0.8

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B

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1

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ii

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D

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iii

i AK4.4PAN02 ii




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se

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20

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tein

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n

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aliz

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0.2

0.4

0.6

0.8

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*

***

***

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Lean

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weig

ht (g

ram

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*

***

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* **

*****

Figure 4

PAN02

p-p38

T-p38

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PAN02

p-ERK

T-ERK

p-AKT

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p-4EBP1

β-actin

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Lean

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ssio

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Note: not all significant differences

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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

+

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ginate

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rea

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100

150

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tion

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mg

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10

20

30

40

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en I

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0

10

20

30

40

50

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Figure 7A

BMI>30BMI<25 PDAC patient samples

B

iii

i iiBMI>30 BMI<25

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Col

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n I

Hya

luro

nan

PDAC patient samples

blood vessel

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Strategies to disrupt obesity-

cancer connection

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C

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50

100

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ii




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

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