title: Dual Pten/Tp53 suppression promotes sarcoma progression by activating Notch signaling.
abstract: Soft tissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in Pten(Δ/+)Tp53(Δ/+) tumors compared with Pten(+/+)Tp53(Δ/+) tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of Pten(Δ/+)Tp53(Δ/+) and shPten-transduced Pten(+/+)Tp53(Δ/+) tumor cells was counteracted by treatment with a γ-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with high-grade sarcoma for targeted treatments.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Guijarro
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.forename: Laura S
authors.initials: LS
authors.lastname: Danielson
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
authors.forename: Frances M
authors.initials: FM
authors.lastname: Vales-Lara
authors.forename: Silvia
authors.initials: S
authors.lastname: Menendez
authors.forename: Dorota
authors.initials: D
authors.lastname: Popiolek
authors.forename: Khushbakhat
authors.initials: K
authors.lastname: Mittal
authors.forename: Jian Jun
authors.initials: JJ
authors.lastname: Wei
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology; D017353:Gene Deletion; D016158:Genes, p53; D005838:Genotype; D057895:Haploinsufficiency; D006801:Humans; D007890:Leiomyosarcoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics*; D051880:Receptors, Notch / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D015398:Signal Transduction / Q000502:physiology; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human