Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment

Matthew L. Goodwin, Huifeng Jin, Krystal Straessler, Kyllie Smith-Fry, Ju Fen Zhu, Michael J. Monument, Allie Grossmann, R Randall, Mario R. Capecchi, Kevin B. Jones

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.

Original languageEnglish (US)
Pages (from-to)851-862
Number of pages12
JournalCancer Cell
Volume26
Issue number6
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Goodwin, M. L., Jin, H., Straessler, K., Smith-Fry, K., Zhu, J. F., Monument, M. J., Grossmann, A., Randall, R., Capecchi, M. R., & Jones, K. B. (2014). Modeling Alveolar Soft Part Sarcomagenesis in the Mouse: A Role for Lactate in the Tumor Microenvironment. Cancer Cell, 26(6), 851-862. https://doi.org/10.1016/j.ccell.2014.10.003