Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity

Abstract

PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.

Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice

“…Cells were then incubated for 4 h at 37 C. Cells were treated with trametinib (16292, Cayman Chemical, Ann Arbor, MI, USA) or rapamycin (13346, Cayman Chemical) at indicated concentrations or a kill control (20% DMSO) for 72 h. Cell viability was determined using the Cell Titer Glo Assay (G7570, Promega, Madison, WI, USA) measuring luminescence with a BioTek Synergy 2 (BioTek/ Agilent, Winooski, VT, USA). The percentage of growth inhibition was calculated using the following formula: (luminescence of treated wellluminescence from kill control)/(luminescence of vehicle treated wellluminescence from kill control) [28].…”

Hyperactive Akt1 Signaling Increases Tumor Progression and DNA Repair in Embryonal Rhabdomyosarcoma RD Line and Confers Susceptibility to Glycolysis and Mevalonate Pathway Inhibitors

“…RMS therapy requires a multimodal approach, consisting of surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, and cyclophosphamide/ifosfamide), resulting in an overall 5-year survival of >70% for localized RMS tumors, while metastatic disease has an unfavorable outcome. Mutations in the PI3K catalytic subunit [ 15 , 16 ], and Fibroblast Growth Factor Receptor 4 (FGFR4) [ 14 , 17 ], and loss of phosphatase and tensin homolog (PTEN) [ 18 ] are found recurrently in RMS to activate the PI3K/Akt/mTOR pathway, which is negatively associated with patient survival [ 19 , 20 , 21 , 22 ]. The Akt through mTOR complex regulates several important processes, including protein synthesis and inhibition of autophagy [ 23 , 24 ], and mechanisms of cell migration, invasion, and metastasis [ 25 , 26 , 27 ].…”

ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology

“…Currently, there are different animal models to study STS [ 3 , 4 , 5 ], which have revealed the implication of key proteins in sarcomagenesis, as in the case of p53 [ 6 ] or the AKT signaling pathway [ 7 , 8 ]. Indeed, most of this experimental observation has been extrapolated to human pathologies, which will certainly have clinical implications in the coming years.…”