Dual Pten/Tp53Suppression Promotes Sarcoma Progression by Activating Notch Signaling

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 Ptenand Tp53in 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. Ptenwas found haploinsufficient, whereas the wild-type allele of Tp53invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in PtenΔ/+Tp53Δ/+tumors compared with Pten+/+Tp53Δ/+tumors. Consistently, Ptensilencing 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 PtenΔ/+Tp53Δ/+and shPten-transduced Pten+/+Tp53Δ/+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 Ptenand Tp53suppression 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.