The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer
•
1 like•1,745 views
Oriol Arqués predoctoral presentation at the 6th Scientific
Recommended
More Related Content
Viewers also liked
Viewers also liked (20)
More from Vall d'Hebron Institute of Research (VHIR)
More from Vall d'Hebron Institute of Research (VHIR) (20)
The Wnt–β-catenin and PI3K-AKT-FOXO3a pathways have a central role in cancer
- 1. b-catenin Confers Resistance to PI3K and AKT Inhibitors and Subverts FOXO3a to Promote Metastasis in Colon Cancer Tenbaum et al. Nat Med. 2012 Oriol Arqués STEM CELLS and CANCER LABORATORY Vall Hebron Institute of Onocology Barcelona, Spain
- 2. b INTESTINAL EPITHELIUM TUMOR Wnt LRP Fz Dsh b b b b b b b b b Lef ON Lef ON TCF/LEF genes TCF/LEF genes 90% of CRC patients present activating mutations in Wnt pathway
- 3. b Other Other Vitamin D NICHE Ligands Ligands LRP Wnt LRP ? ? Fz CANCER Dsh CELL b b b b b b b LEF VDR FOXO3a ? TCF/LEFgenes VDR genes Target Genes ? Target genes ? CELL FATE
- 4. What is the role of FOXO3a/b-catenin crosstalk in colon cancer?
- 5. b a b b-cat b-cat FOXO3a FOXO3a b-cat b-cat FOXO3a Merge FOXO3a Merge c 0.08 P = 0.0177 * d 100 Nuclear Nuclear FOXO3a & b-cat High 0.06 FOXO3a & b-catenin Low Patients surviving (%) content (r. u. ) 80 0.04 60 40 0.02 20 n = 113 P = 0.0003 0 0 n= 13 22 135 14 0 12 24 36 48 60 72 84 96 108 120 ADENOMA I+II III+IV LIVER Time (months) CARCINOMA METASTASIS Tenbaum et al. Nat Med. 2012
- 6. b Normal cell APC -/- ADENOMA LEVELS of REGULATION APC -/-; K-RasV12 APC -/- - GENETIC NUCLEAR b-CATENIN NUCLEAR b-CATENIN - NICHE NUCLEAR FOXO3a Stress or PI3K/AKT Inhibitors? Proliferation APOPTOSIS METASTASIS PROLIFERATION HETEROGENEOUS CARCINOMA Tenbaum et al. Nat Med. 2012
- 7. b WNT OXIDATIVE GROWTH EGFR/PI3K/AKT INHIBITORS ESTRESS FACTORS INHIBITORS RTK XAV-939 CETUXIMAB b Axin JNK RAS b PI3K BKM-120 FOXO3a b b AKT API-2 b b LEF FOXO3a ON ON PROLIFERATION APOPTOSIS CYCLE ARREST & METASTASIS CELL FATE
- 8. b a E-cadh Phalloidin b c e f Tenbaum et al. Nat Med. 2012
- 9. b a PATIENT XENOGRAFT b PATIENT XENOGRAFT c 40 T49 T49 T49 T49 T49 APOPTOSIS (% Annexin V positive cells) 30 20 10 0 30 T61 T61 T61 T61 T61 20 10 β-cat 0 XAV-939 - + - + - + - + LY-294002 - - + + - - - - d BKM120 - - - - + + - - API-2 - - - - - - + + e Time (days) Time (days) Tenbaum et al. Nat Med. 2012
- 10. b Tenbaum et al. Nat Med. 2012
- 11. GENOTYPING NUCLEAR b-CATENIN PI3K & AKT RESPONSE PI3K & AKT INHIBITORS APOPTOSIS SEQUENOM ANALYSIS INHIBITORS + WNT INHIBITORS LOW CRC PATIENT APC CTNNB1 AXIN1 PTEN PI3KA RESISTANCE AKT METASTASIS HIGH OR
- 14. b All-in-one Lentivirus: TetON-Flag-bcatS33Y-IRES-EGFP b-cat IRES EGFP rtTA2 TRE hPGK1 FLAG S33Y DOX 4OHT E-cadh E-cadh b b b rtTA2 ER FOXO3a b b b rtTA2 LEF x ER FOXO3a b-cat eGFP TCF/LEF Unknown FOXO S33Y Target genes Target genes Target genes
- 15. b DLD-1Fb-C7 VEHICLE 4OHT DOX 4OHT + DOX b PROLIFERATION APOPTOSIS FOXO3a dominant b-catenin dominant DLD1 -1Fb-C7 XENOGRAFT DLD1 -1Fb-C7 XENOGRAFT Tenbaum et al. Nat Med. 2012
- 16. b E-cadherin relocation Increased cell motility Increased cell adhesion VEHICLE 4OHT A B B A DOX 4OHT+DOX E-cadherin Phalloidin 4OHT - + - + DOX - - + + E-cadh - 120 (Clone 36) E-cadh - 120 (HECD1) Snail1 - 28 Tubulin - 50 Tenbaum et al. Nat Med. 2012