A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells

Cancer Discov. 2015 Apr;5(4):396-409. doi: 10.1158/2159-8290.CD-14-1022. Epub 2015 Jan 22.

Abstract

The regulatory factors governing adult mesenchymal stem cell (MSC) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal forms of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here, we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSC transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma, with important therapeutic implications.

Significance: The paucity of therapeutic options for the treatment of sarcoma calls for a rapid and effective preclinical assessment of new therapeutic modalities. We have here developed a new platform to deconstruct the molecular genetics underlying the pathogenesis of sarcoma and to evaluate in vivo the efficacy of novel targeted therapies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Calcium-Binding Proteins
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunophenotyping
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological*
  • Phenotype
  • Sarcoma / genetics*
  • Sarcoma / metabolism
  • Sarcoma / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Zbtb7a protein, mouse