IMPLICACIÓN BIOLÓGICA DE LA CTCS Y LOS ÁCIDOS NUCLEICOS …-+CTCs+y... · 2016. 10. 3. ·...
Transcript of IMPLICACIÓN BIOLÓGICA DE LA CTCS Y LOS ÁCIDOS NUCLEICOS …-+CTCs+y... · 2016. 10. 3. ·...
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IMPLICACIÓN BIOLÓGICA DE LA
CTCS Y LOS ÁCIDOS
NUCLEICOS CIRCULANTES
Paloma Bragado Domingo, PhD
SEAP-IAP-Reunión De Primavera
“Biopsia Líquida: Un Nuevo Reto Para
El Patólogo Y El Oncólogo
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CANCER IS A SYSTEMIC AND HETEROGENEOUS
DISEASE
DTCs at secondary organs:Metastasis precursor cells
Adapted from Alberter, B et al., (2016) Expert review of Molecular Diagnostics, 16:1,25-38.
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Tum
or m
ass
Primary tumor Minimal residual disease
Disease free period/resistance to therapyLate DTCs Disseminated tumor cell dormancy
metastasis
CANCER AS AN EVOLUTIONARY DISEASET
umor
mas
s
Surgery and therapy
Timeyears Months years decadesEarly
DTCs
Late DTCs Disseminated tumor cell dormancy
Bragado P, Nat Rev Cancer. 2014
ZZ
Z
ZZ
Z
ZZ
Z
G0-G1 arrest
Survival
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CLINICAL EVIDENCES FOR TUMOR DORMANCY
Klein, C. A.. Curr. Opin. Genet. Dev. 21, 42–49 (2010).
Aguirre-Ghiso, J. A. Nature Rev. Cancer 7, 834–846 (2007)
Wolfgang Janni et al. Clin Cancer Res 2011;17:2967-2976
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WHAT ARE THE MOLECULAR
MECHANISMS THAT REGULATE DTCS
DORMANCY?DORMANCY?
CAN MICROENVIRONMENTAL SIGNALS
REGULATE DTCS DORMANCY?
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HEp3-GFP
HEp3-GFP Primary tumor + surgery
~2weeks
~4weeks
HEP3 MINIMAL RESIDUAL DISEASE MODEL
73
81
24
5,65,6
14 Lungs
Lymph Nodes
bone Marrow
Liver
Spleen
Others
DTCs incidence
DTCs?
Lungs
Bone Marrow
29.15 ± 9.1
(55.8± 17.3)*104 VimentinP-H3DAPI
p27CKDAPI
GFP/DAPI
DTCs
P-H3CK
DAPI
Bragado P, et al., (2013) Nat Cell Biol.;15(11):1351-61.
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BM-D
QUIESCENCE OF BM DTCS DERIVED CELLS
DEPENDS ON P38 ACTIVATION AND DEC2 INDUCTION
BM-HEp3
In vitro expansion
Lu
ng
sB
on
e M
arro
w
DTCs
20 Generations
20 Generations
15% Efficiency In vivo
α
DEC2
p53
Low expression
High Expression
Fold change: -5.6 +2.6
PT
-3
Lu
-7
BM
-3
Lu
-6
PT
-4
BM
-D
4T1
4T07
F3I
I
Lu-HEp3Lung DTCs 100% tumorigenic in vivo
BM DTCs 73% dormant in vivo
Lu
ng
s
100% Efficiency
Bragado P, et al., (2013) Nat Cell Biol.;15(11):1351-61.
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% o
f p
27+
cells 100
8060
*
TGFβ2
:mAbPI-IgG α-TGFβ2
BM CM
Bone Marrow
P38 ,TGF 2 AND TGF R3 REGULATE DTCS
DORMANCY
α β β
Control
SB203580
% o
f p
27+
6040200
Si scr Si p38α
*
Lungs
Bragado P, et al., (2013) Nat Cell Biol.;15(11):1351-61.
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Dormancy inducing factors: P-p38, TGFβ2, TGFβR3, DEC2, p27, NR2F1, SOX9
TGF 2 / TGF 1 RATIO DICTATES DISSEMINATED
TUMOUR CELL FATE IN TARGET ORGANS THROUGH TGF R3 AND P38 / SIGNALLING
α ββ
ββ
Can we use the expression of this dormancy inducing factors to predict relapse and stratify
patients?
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DORMANCY SIGNATURES PREDICT METASTASIS IN
OESTROGEN RECEPTOR POSITIVE BREAST CANCER
Kim RS, et al., PLoS One. 2012;7(4):e35569
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DTCS FROM PATIENTS WITH NO EVIDENCE OF DISEASE
WERE SIGNIFICANTLY ENRICHED FOR DORMANCY-RELATED GENES
Chéry L et al. Oncotarget. 2014 Oct 30;5(20):9939-51.
Sosa MS et al., Nat Commun. 2015 Jan 30;6:6170.
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BONE MARROW AS A RESERVOIR FOR DTCS: A SPECIAL
SOURCE FOR LIQUID BIOPSY DTC MONITORING TO TREAT
DORMANT RESIDUAL DISEASE
Adapted from Pantel K, Alix-Panabières C. Bonekey Rep. 2014 Nov 19;3:584.
Aguirre-Ghiso, J et al., 2013 Mar;19(3):276-7.
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DTCS VS CTCS
� Do CTCs express dormancy markers?DTCs Limitations:• Repeated sampling of BM or
LN is difficult• DTCs reflect only the
situation in the BM• However the reflect the
”history” of tumour cell dissemination
� Do dormant DTCs disseminate and become CTCs?
CTCs advantages:• Easy access• Minimal invasiveness• Minimal Risk• Provide information on
metastatic cells derived from various distant sites
• However, they represent only a snapshot of tumour cell dissemination
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MICRO-RNAS AND DORMANCY
� Do Patient DTCs also overexpress miR 190, miR 580 and miR 588?
� Can we detect those miR in blood?
� Would their expression correlate with the dormancy phase?dormancy phase?
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Laboratory of signaling and metastasisJulio Aguirre Ghiso•Yeriel Estrada •Alvaro Avivar Valderas •Soledad Sosa•Alfred Adomako•Kathryn Harper Molecular and Translational •Kathryn Harper•Falguni Parikh•Nina Linden•Veronica Calvo•Denis Schewe•Aparna Ranganathan•Wen Huei-Chi•David Cannan
Molecular and Translational oncology Pere Gascon•Raul Alonso•Gemma Fuster•Mario Mancino •Patricia Fernandez •Arantzazu Zubeldia•Estel Enreig •Anna Lopez•Elisabet Ametller