Uncovering metabolism in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

Signaling pathways that overactivate metabolism and drive neoplasia, in rhabdomyosarcoma

“…RMS tumors share several molecular signatures with common malignancies that would predict important metabolic adaptations. Molecular hallmarks having impact on RMS metabolism and driving metabolic changes in RMS are: Pax3-Foxo1 oncoprotein, deliberate activation of RTK pathways, loss of p53 activity and oxidative stress pathways 39 .…”

“…In the metabolic context, Pax3-Foxo1 has been shown to drive transcription of GLUT4 gene, thereby eliciting increased glucose uptake 43 . It also has the ability to drive the transcription of genes like fibroblast growth factor receptor 4 (FGFR4) and insulin-like growth factor 2 (IGF-2) as well as the ability to elicit downregulation of PTEN gene 39 . Thus, fusion-positive RMS' are characterized by sustained activation of the RTK/RAS/PI3K/AKT/mTOR pathway; in addition these tumors often carry high copy number of N-Myc gene and exhibit IGF-2 overexpression due to loss of imprinting (LOI) at 11p15.5 locus 39 .…”

“…It also has the ability to drive the transcription of genes like fibroblast growth factor receptor 4 (FGFR4) and insulin-like growth factor 2 (IGF-2) as well as the ability to elicit downregulation of PTEN gene 39 . Thus, fusion-positive RMS' are characterized by sustained activation of the RTK/RAS/PI3K/AKT/mTOR pathway; in addition these tumors often carry high copy number of N-Myc gene and exhibit IGF-2 overexpression due to loss of imprinting (LOI) at 11p15.5 locus 39 . The activity of AKT in ARMS cells with a Pax3-Foxo1-dependent transcription of the carnitine palmitoyltransferase gene (CPT1A), the outer mitochondrial enzyme responsible for the formation of acyl carnitines, was reported to facilitate lipid degradation 44 .…”

“…Both fusion-positive and -negative RMS subsets share a deliberate activation of RTK-dependent pathways 45 . Different lines of evidence indicate that the PI3K/AKT and ERK1/2 pathways, often concurrently with the HIF pathway, play a central role for RMS progression 39 .…”

“…A gene signature consistent with the "p53 off" state has been significantly found in fusion-negative RMS with an incidence from 5% to 19% 45,46 , whereas to a lesser extent in fusion-positive tumors 46,47 . Besides glucose consumption, further experimental evidence is required to address the question of whether p53 loss may impact other key metabolic pathways in RMS 39 .…”