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

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Presentation on theme: "Dual PTEN/P53 suppression promotes high grade sarcomas by activating Notch Eva Hernando, Ph.D."— Presentation transcript:

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

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

3 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) Targeted sequencing revealed low incidence of mutations in classical ‘cancer genes’ 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 Tagln-cre/ Pten wt p53 wt Tagln-cre/ Pten L/+ p53 L/+ Tagln-cre/ Pten L/+ p53 wt Tagln-cre/ Pten wt p53 L/+ Tagln-cre/ Pten L/L p53 wt Tagln-cre/ Pten wt p53 L/L Tagln-cre +/+ Pten L/L p53 L/L Tagln-cre +/- /Pten L/+ p53 L/+ F1Tagln-cre +/- /Pten L/+ p53 L/+ F2 F0

7 Pten  /+ p53  /+ mice have shorter overall survival than Pten  /+ p53  /+ Guijarro et al., AJP 2013 Hernando et al., Nat Med 2007

8 Pten  /+ p53  /+ mice h ave increased sarcoma incidence compared to Pten  /+ p53  /+ Guijarro et al., AJP 2013

9 Pten  /+ p53  /+ HGS histologically resemble the equivalent human lesions Guijarro et al., AJP 2013

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

11 Tagln-cre is also expressed in mesenchymal stem cells

12 Murine HGUPS have complex karyotypes

13 Liver Pancreas Lung Pten  /+ p53  /+ HGUPS are highly metastatic

14 Pten is haploinsufficient for sarcoma tumor progression No mutation Pten  /+ p53  /+ Pten  /+ p53  /+

15 Which advantage does Pten downregulation confer to p53 deficient sarcomas?

16 Pten  /+ /p53  /+ bone-marrow mesenchymal stem cells display higher clonability and proliferation Pten L/+ /p53 L/+ and Pten  + /p53 L/+ bone marrow-derived mouse mesenchymal stem cells + Adeno-cre infection Colony formation assayProliferation 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  /p53  /+ tumor cells increases clonogenic capacity and invasion

18 The Notch signaling pathway is up-regulated in Pten Δ/+ Tp53 Δ/+ murine HGUPS

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

21 shPten pro-oncogenic effects are counteracted by Notch inhibition Colony formation assayinvasion 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 Hernando Lab Maria V. Guijarro Laura Danielson Miguel Segura Martha Vega Avital Gaziel Silvia Menendez Luca Paoluzzi Doug Hanniford Raffaella Di Micco Lisa Koetz Barbara Fontanals Elena Sokolova Vivien Low Olivia Blackburn Rana Moubarak Veronica Davalos Praveen Agrawal Collaborators Sonika Dahiya Jian Jun Wei Carlos Cordon-Cardo Pier Paolo Pandolfi 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


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