Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment

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 potent driver of alveolar soft part sarcomagenesis.