Catalytic-Independent And Subtype-Specific Roles Of Fructose-1,6-Bisphosphatase 2 In Sarcoma Growth

Fructose-1,6-bisphosphatase 2 (FBP2), a rate limiting gluconeogenic enzyme, is primarily expressed in skeletal muscle yet its physiological contribution in this tissue is not fully established. To investigate its function, we examined FBP2 expression in different skeletal muscle fiber types and in myogenic progenitor populations. Using immunohistochemical and transcriptomic analyses, we show that FBP2 is selectively expressed in fast-twitch skeletal muscle fibers and is absent in myogenic progenitors. Ectopic FBP2 expression in myoblasts impairs differentiation and reduces mitochondrial mass, suggesting that FBP2 must be temporally restricted for myogenesis. FBP2 also has emerging roles in sarcoma malignancy. Altered cancer metabolism influences tumor growth through both enzymatic and non-enzymatic mechanisms; however, FBP2’s catalytic activity-independent functions are not fully defined. Here, we demonstrate that FBP2 exerts subtype-specific effects on sarcoma growth through both catalytically activity-dependent and -independent mechanisms. Ectopic expression of wildtype or a novel catalytically inactive FBP2 mutant (E98A) suppresses proliferation and tumor growth in liposarcoma and fibrosarcoma models in vitro and in vivo. In contrast, FBP2 appears to promote tumor growth in an autochthonous LSL-KrasG12D/+;Trp53fl/fl (KP) model of undifferentiated pleiomorphic sarcoma (UPS), reflecting human epidemiological data. Collectively, these findings reveal FBP2 as a context-dependent regulator of metabolic signaling and sarcoma progression, highlighting its potential as a prognostic biomarker in STS.

Author dc:creator

• Nance, Bailey

Advisor dc:contributor.advisor

• Simon, M. Celeste

• Biology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62716

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62716