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
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.
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
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
WHAT ARE THE MOLECULAR
MECHANISMS THAT REGULATE DTCS
DORMANCY?DORMANCY?
CAN MICROENVIRONMENTAL SIGNALS
REGULATE DTCS DORMANCY?
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.
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.
% 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.
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?
DORMANCY SIGNATURES PREDICT METASTASIS IN
OESTROGEN RECEPTOR POSITIVE BREAST CANCER
Kim RS, et al., PLoS One. 2012;7(4):e35569
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.
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.
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
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?
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
Top Related