ONCOSTATIN M RECEPTOR IS A

NOVEL THERAPEUTIC TARGET IN

TRIPLE NEGATIVE BREAST CANCER

Maria Muñoz Caffarel

Biodonostia Health Research Institute, San Sebastian, Spain

maria.caffarel@biodonostia.org

OSM:OSMR signalling

OSMROSM

gp130

MAPK pathway

Pi3K pathway

Adapted from Caffarel & Coleman, J Pathol 2014

Pro-malignant effects of OSMR signalling

Aims of the project

• Is OSMR a biomarker in breast cancer?

• Does OSMR signalling promote tumour

progression?

• Can we target tumour progression by

blocking OSMR signalling?

OSMR

Biomarker

MechanismTherapy

OSMR is a prognostic factor in ER neg breast cancer

METABRIC dataset (n=1981)

Collaboration with Carlos Caldas, CRUK, Cambridge, UK

OSM is over-expressed in ER

negative and basal tumours� METABRIC dataset (n=1462)

p < 0,0001 p < 0,05

basal HER2 luminal normal

� TCGA dataset (n=547)ANOVA: 0,006

p = 0,011

Collaboration with Arkaitz Carracedo, Biogune

OSMR pathway is over expressed

in basal breast cancer cell lines

0

2

4

6

8

Fo

ldin

du

ctio

n

OSMR expression

luminal basal0

2

4

6

8 OSMRp = 0.006

fold

ind

uct

ion

luminal basal0

1

2

3

4 OSMp < 0.0001

fold

ind

uctio

n

luminal basal0

1

2

3

4 IL6p = 0.039

fold

ind

uct

ion

OSMR is expressed by tumour cells

Normal breast Infiltrating breast tumours

OSM is expressed by the tumour stroma

Normal breast Infiltrating breast tumours

Mammary

epithelial cells

Tumour stromaTumour cells

OSM expression increases after chemotherapy

Quail D. and Joyce J,

Nature Medicine 2013

The tumour microenvironment has a key role in all

the steps of tumour progression

Do stromal cells contribute to OSMR

signalling in cancer cells?

Collaboration with Paloma Bragado, IDIBAPS, Barcelona

� Do CAFs secrete OSM in co-culture with breast cancer cells?

� Do they have an effect in the invasion, migration, pro-angiogenic phenotype

of breast cancer cells?

Do stromal cells (fibroblasts) contribute to

OSMR signalling in cancer cells?

luminal basal fibroblasts0

5

10

15 OSMRANOVA = 0.0019

fold

ind

uct

ion

luminal basal fibroblasts0

20

40

60

80 OSMANOVA = 0.0020

fold

ind

uct

ion

0,00

0,50

1,00

1,50

2,00

si NTPC

PBS

si NTPC

OSM

si OSMR

PBS

si OSMR

OSM

IL-6

OSM activates STAT3 and induces the

expression of pro-malignant factors in basal

breast cancer cells

MDA-MB-231 cells

0,00

0,50

1,00

1,50

2,00

2,50

3,00

si NTPC

PBS

si NTPC

OSM

si OSMR

PBS

si OSMR

OSM

fold

in

du

ctio

n

OSMR

0,00

0,50

1,00

1,50

2,00

2,50

si NTPC

PBS

si NTPC

OSM

si OSMR

PBS

si OSMR

OSM

fold

in

du

ctio

n

VEGF

0,00

0,50

1,00

1,50

2,00

2,50

si NTPC

PBS

si NTPC

OSM

si OSMR

PBS

si OSMR

OSM

SNAIL

OSM treatment ng/ml

OSMR

pUNO-Control pUNO-hOSM 0

1

2

3

4

5

STAT3

pUNO-Control pUNO-hOSM 0.0

0.5

1.0

1.5

2.0

2.5SNAIL

pUNO-Control pUNO-hOSM 0

2

4

6

8

10

VEGF

pUNO-Control pUNO-hOSM 0.0

0.5

1.0

1.5

2.0

2.5

Does OSMR signalling promote tumour progression?MDA-MB-231:

+ hOSM (OSM over-expressing cells)

+ hControl (Control cells)

p=0.0020

0 10 20 30 40 500

50

100

150controlhOSM

Time (days)

Tum

our

fre

e an

imal

s (%

)

0 10 20 30 40 5020

22

24

26

28

30

h Controlh OSM

Time (days)

Bo

dy

wei

ght

(g)

Tumour onsetBody weight

Activation of OSMR induces tumour formation

Control tumour and

mammary glands

OSM tumours

no OSM OSM over-expressing0

2

4

6

p = 0.0002

OS

MR

mR

NA

(fo

ld c

han

ge)

no OSM OSM over-expressing0.0

0.5

1.0

1.5

2.0

2.5p = 0.01

ST

AT

3 m

RN

A (

fold

cha

nge)

no OSM OSM over-expressing0

5

10

15

p = 0.10

IL6

mR

NA

(fo

ld c

hang

e)

no OSM OSM over-expressing0

1

2

3

4

5

p = 0.16

VE

GFA

mR

NA

(fo

ld c

han

ge)

OSMR pathway is activated in

OSM-expressing tumours

Immunocompetent mouse models

MMTV-PyMT

MMTV-Neu

MMTV-PyMTMMTV-Neu

Lung metastases

OSMR KO

X

Study impact of OSMR deletion on:

- Tumour onset

- Tumour growth

- Lung metastasis

- Response to drugs

Generation of a breast cancer genetic

model with OSMR knock out

Estrogen negative breast cancer

OSM

OSMRDecreased

overall survival

Stromal cells

OSM

OSM

OSM

OSM OSM

Conclusions

OSMR

Biomarker

MechanismTherapy

Conclusions

Future work

OSM:OSMR interactions?

� Study the contribution of the tumour

microenvironment to OSMR activation

� Immunocompetent mouse models

� Pre-clinical testing of OSM:OSMR

neutralizing antibodies

Angela Araujo

Miren Iraeta

Isabel Álvarez-López (Hospital Donostia)Ander Urruticoechea (Onkologikoa)Ricardo Rezola (Onkologikoa)Charles Lawrie (Biodonostia)Eva González-Suarez (IDIBELL, Barcelona)

Ana Esnal

maria.caffarel@biodonostia.org

Andrea Abaurrea

Nicholas Coleman (University of Cambridge)Oscar Rueda (CRUK, Cambridge, UK)Alejandra Bruna (CRUK, Cambridge, UK)Gema Moreno (MD Anderson, Madrid)Paloma Bragado (IDIBAPS, Barcelona)Arkaitz Carracedo (Biogune, Bilbao)

Representative tumour Representative reactive lymph node

Do stromal cells contribute to OSMR

signalling in cancer cells?

Collaboration with Paloma Bragado, IDIBAPS, Barcelona

� Do CAFs secrete OSM in co-culture with breast cancer cells?

� Do they have an effect in the invasion, migration, pro-angiogenic phenotype

of breast cancer cells?

Do stromal cells (fibroblasts) contribute to

OSMR signalling in cancer cells?

luminal basal fibroblasts0

5

10

15 OSMRANOVA = 0.0019

fold

ind

uct

ion

luminal basal fibroblasts0

20

40

60

80 OSMANOVA = 0.0020

fold

ind

uct

ion