title: Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment.
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.
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Goodwin
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Krystal
authors.initials: K
authors.lastname: Straessler
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kyllie
authors.initials: K
authors.lastname: Smith-Fry
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Ju-Fen
authors.initials: JF
authors.lastname: Zhu
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monument
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Allie
authors.initials: A
authors.lastname: Grossmann
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.affiliation: Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Capecchi
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA; Center for Children's Cancer Research at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: kevin.jones@hci.utah.edu.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019344:Lactic Acid / Q000378:metabolism*; D051379:Mice; D009374:Neoplasms, Experimental; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D018234:Sarcoma, Alveolar Soft Part / Q000378:metabolism / Q000473:pathology*; D059016:Tumor Microenvironment
chemical_list: C422743:ASPSCR1 protein, human; C478539:Aspscr1 protein, mouse; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C069203:TFE3 protein, human; C068486:Tcfe3 protein, mouse; D019344:Lactic Acid