The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer
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b-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer Oriol Arqués STEM CELLS and CANCER LABORATORY Vall Hebron Institute of Onocology Barcelona, Spain Tenbaum et al. Nat Med. 2012
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Oriol Arqués predoctoral presentation at the 6th Scientific
Transcript of The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer
b-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer
Oriol Arqués STEM CELLS and CANCER LABORATORY
Vall Hebron Institute of Onocology Barcelona, Spain
Tenbaum et al. Nat Med. 2012
INTESTINAL EPITHELIUM TUMOR
b
b b
Dsh
LRP
Wnt
Fz
TCF/LEF genes
Lef b
ON
b
b b
TCF/LEF genes
Lef b
ON
b
b
90% of CRC patients present activating mutations in Wnt pathway
b
Vitamin D
b
b b
LRP
Wnt
Dsh
Fz
TCF/LEFgenes
LEF
b
VDR genes
VDR
b
Target Genes ?
FOXO3a b
Target genes ?
? b
NICHE
CELL FATE
CANCER CELL
?
Other Ligands
LRP
?
Other Ligands
n = 13 22 135 14
ADENOMA
CARCINOMA
I+II III+IV LIVER
METASTASIS
0.08
0.04
0
0.06
0.02
*= 0.0177P
Time (months)0 12 24 36 48 60 72 84 96 108 120
0
20
40
60
80
100 HighLow
P = 0.0003
n = 113
Pati
en
ts s
urv
ivin
g (
%)
Nu
cle
ar
FO
XO
3a &
b-c
at
co
nte
nt
(r.
u. )
FOXO3a FOXO3a
b-cat b-cat
FOXO3a FOXO3a
b-cat b-cat
Merge Merge
Nuclear
FOXO3a & b-catenin
a b
c d
Tenbaum et al. Nat Med. 2012
b
APC -/-; K-RasV12
METASTASIS Proliferation APOPTOSIS
- NICHE
- GENETIC
LEVELS of REGULATION
HETEROGENEOUS CARCINOMA
Normal cell APC -/-
APC -/-
ADENOMA
Stress or
PI3K/AKT Inhibitors?
PROLIFERATION
NUCLEAR FOXO3a
b
NUCLEAR b-CATENIN NUCLEAR b-CATENIN
Tenbaum et al. Nat Med. 2012
b
CELL FATE
FOXO3a ON
OXIDATIVE ESTRESS
JNK
FOXO3a
RAS
GROWTH FACTORS
RTK
EGFR/PI3K/AKT INHIBITORS
PI3K
AKT
APOPTOSIS
API-2
CETUXIMAB
b
b
b b
PROLIFERATION
b
ON
WNT INHIBITORS
Axin b
CYCLE ARREST & METASTASIS
LEF
XAV-939
BKM-120
b
e
AP
OP
TOSI
S (%
An
nex
in V
po
siti
ve c
ells
)
Tenbaum et al. Nat Med. 2012
T4940
30
20
10
PATIENT XENOGRAFTPATIENT XENOGRAFT
0
T49 T49T49 T49
c
T6130
20
10
0
T61 T61 T61 T61
β-cat
LY-294002XAV-939
++
+--
--
API-2 --- -
+
+ +
--
-+
BKM120
+--
-
--++ --- -- -
a
Time (days) Time (days)
d
b
CRC PATIENT
NUCLEAR b-CATENIN ANALYSIS
PI3K & AKT INHIBITORS
PI3K & AKT INHIBITORS + WNT INHIBITORS
RESISTANCE METASTASIS
RESPONSE APOPTOSIS
OR
HIGH
LOW
GENOTYPING SEQUENOM
APC CTNNB1 AXIN1
PTEN PI3KA AKT
Fundación Olga Torres
b
TCF/LEF Target genes
ER FOXO3a
b
DOX
b-cat S33Y
rtTA2
x LEF rtTA2
4OHT
b b
ER FOXO3a
FOXO Target genes
Unknown Target genes
eGFP
E-cadh b
E-cadh
b b
rtTA2
TRE
IRES EGFP
hPGK1
b-cat
FLAG S33Y
All-in-one Lentivirus: TetON-Flag-bcatS33Y-IRES-EGFP
b
VEHICLE 4OHT DOX 4OHT + DOX
DLD-1Fb-C7
APOPTOSIS
b-catenin dominant
PROLIFERATION
FOXO3a dominant
DLD1 -1Fb-C7 XENOGRAFT DLD1 -1Fb-C7 XENOGRAFT
b
Tenbaum et al. Nat Med. 2012
E-cadherin relocation
E-cadherin Phalloidin
- - 4OHT + +
E-cadh (Clone 36)
Tubulin
Snail1
DOX + + - -
E-cadh (HECD1)
- 120
- 120
- 28
- 50
VEHICLE
DOX
4OHT
4OHT+DOX
Increased cell adhesion
A
A B B
Increased cell motility
b
Tenbaum et al. Nat Med. 2012
