1 / 24

Dual PTEN/P53 suppression promotes high grade sarcomas by activating Notch

Dual PTEN/P53 suppression promotes high grade sarcomas by activating Notch. Eva Hernando, Ph.D. Challenges in the study of high grade sarcoma and leiomyosarcoma. Genomic complexity Low number of known recurrent genetic mutations Limited enrolment of patients in clinical trials.

parker
Download Presentation

Dual PTEN/P53 suppression promotes high grade sarcomas by activating Notch

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Dual PTEN/P53 suppression promotes high grade sarcomas by activating Notch Eva Hernando, Ph.D.

  2. Challenges in the study of high grade sarcoma and leiomyosarcoma • Genomic complexity • Low number of known recurrent genetic mutations • Limited enrolment of patients in clinical trials • better understanding of the molecular basis • mouse models that recapitulate human disease • Preclinical testing (immunotherapy)

  3. Targeted sequencing revealed low incidence of mutations in classical ‘cancer genes’ • N=40 specimens(NYU School of Medicine and Northwestern University) • Platform: OncoMap3 core and extended panels (1047 mutations in 116 genes) • 73 candidate mutations on 44 genes • 6 confirmed mutations on 2 genes: • TP53 (one V157F and two R273C amino acid substitutions). • a low-frequency germ-line single-nucleotide polymorphism in EGFR (S703F) Guijarro et al., AJP 2013

  4. Partial PTEN and TP53 deletions are common in HGUPS and LMS Barretina et al., Nat Gen 2010 Guijarro et al., AJP 2013

  5. PTEN and TP53 expression is commonly downregulated in HGUPS and LMS Guijarro et al., AJP 2013

  6. Smooth-muscle specific conditional inactivation of Pten and p53 F0 PtenL/L p53L/L Tagln-cre+/+ F1 Tagln-cre+/- /PtenL/+p53L/+ Tagln-cre+/- /PtenL/+ p53L/+ Tagln-cre/ Ptenwtp53wt Tagln-cre/ PtenL/+p53L/+ Tagln-cre/ PtenL/+ p53wt Tagln-cre/ Ptenwtp53L/+ Tagln-cre/ PtenL/Lp53wt Tagln-cre/ Ptenwtp53L/L F2

  7. PtenD/+p53D/+mice have shorter overall survival than Pten+/+p53D/+ Guijarro et al., AJP 2013 Hernando et al., Nat Med 2007

  8. PtenD/+p53D/+mice have increased sarcoma incidence compared to Pten+/+p53D/+ Guijarro et al., AJP 2013

  9. PtenD/+p53D/+HGS histologically resemble the equivalent human lesions Guijarro et al., AJP 2013

  10. Tagln-cremarks smooth muscle cells Tagln-cre+/+ x ROSA26-loxP-STOP-loxP-LacZ Guijarro et al., 2013

  11. Tagln-creis also expressed in mesenchymal stem cells

  12. Murine HGUPS have complex karyotypes

  13. PtenD/+p53D/+HGUPS are highly metastatic Liver Pancreas Lung

  14. Pten is haploinsufficient for sarcoma tumor progression PtenD/+p53D/+ Pten+/+p53D/+ No mutation

  15. Which advantage does Ptendownregulation confer to p53deficient sarcomas?

  16. PtenD/+/p53D/+ bone-marrow mesenchymal stem cells display higher clonability and proliferation PtenL/+/p53L/+and Pten+/+/p53L/+bone marrow-derived mouse mesenchymal stem cells + Adeno-cre infection Colony formation assay Proliferation assay Both, acute and genetically induced concomitant inactivation of Pten and P53 leads to increased clonogenic and proliferative capacity of mesenchymal stem cells

  17. Pten suppression in Pten+/+/p53D/+ tumor cells increases clonogenic capacity and invasion

  18. The Notch signaling pathway is up-regulated in PtenΔ/+Tp53Δ/+ murine HGUPS

  19. The Notch signaling pathway is up-regulated in PtenΔ/+Tp53Δ/+ murine HGUPS

  20. Gamma-secretase inhibition suppresses the clonogenic and invasive potential of tumor cells GSI Colony formation assay

  21. shPtenpro-oncogenic effects are counteracted by Notch inhibition Colony formation assay invasion assay

  22. Model of molecular classification of high grade sarcoma patients for targeted therapies

  23. Conclusions • Conditional inactivation of Pten and p53 in mouse mesenchymal progenitors recapitulates the histological and cytogenetic features of human HGUPS and LMS • Pten deficiency confers increased clonogenic and invasive potential to p53 heterozygous sarcoma cells • Pten suppression in p53 deficient MSCs and tumor cells triggers Notch signaling • Gamma-secretase inhibitors negate the pro-oncogenic effects of Pten suppression in p53 deficient sarcoma cells • PTEN/TP53 deficient HGUPS may be susceptible • to Notch inhibition

  24. Collaborators SonikaDahiya JianJun Wei Carlos Cordon-Cardo Pier Paolo Pandolfi Hernando Lab Maria V. Guijarro Laura Danielson Miguel Segura Martha Vega AvitalGaziel Silvia Menendez Luca Paoluzzi Doug Hanniford Raffaella Di Micco Lisa Koetz Barbara Fontanals Elena Sokolova Vivien Low Olivia Blackburn RanaMoubarak Veronica Davalos Praveen Agrawal Funding American Cancer Society Edna´s Foundation of Hope Liddy Shriver Sarcoma Intiative Sarcoma Foundation of America Melanoma Research Alliance DOD NIH/NCI NIH/NIAMS

More Related