Study of the mechanisms of sarcoma progression using mouse models and in vitro manipulation of mesenchymal stem cells

The underlying genetic defects and the cell of origin of most human sarcomas remain unknown. Recently, alterations in the PI3K-Akt pathway have been identified in certain sarcoma subtypes. For instance, loss of heterozygosity of 10q (containing the PTEN genomic locus) has been frequently observed in human leiomyosarcomas (LMS). In addition, we have found evidences of PI3K/Akt constitutive signaling in human LMS. To determine the role of aberrant PI3K-Akt signaling in LMS pathogenesis, we have genetically inactivated Pten in the mouse smooth muscle (SM). Resultant animals carrying homozygous deletion of both PTEN alleles developed widespread SM hyperplasia, abdominal and retroperitoneal LMS with a very rapid onset and elevated incidence. This finding has led us to postulate that alterations in the PTEN-Akt pathway might constitute the initiation event of SM transformation. The present proposal will be focused on unraveling the subsequent molecular alterations required for sarcoma progression. Aim 1. Determine the genetic alterations required for sarcoma progression in mouse models of leiomyosarcoma. Aim 2. Study the capacity of Pten loss and subsequent molecular events to interfere with the differentiation program and/or induce neoplastic transformation of adult mesenchymal stem cells maturing into smooth muscle in vitro. The ultimate goal of this proposal is to establish the significance and the sequential order of events at the origin and progression of leiomysarcomas. Moreover, we will determine the effect of those alterations when introduced at specific moments of the SM differentiation process.