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

Area of Science:

• Oncology
• Molecular Biology
• Developmental Biology

Background:

• PTEN alterations, including hypermethylation and copy number loss, are frequent in fusion-negative rhabdomyosarcoma (FN-RMS).
• The precise role of PTEN loss in FN-RMS pathogenesis and tumor cell differentiation remains incompletely understood.

Purpose of the Study:

• To investigate the functional consequences of Pten deletion in a mouse model of FN-RMS.
• To elucidate the molecular mechanisms by which PTEN loss influences tumor characteristics and differentiation.
• To identify potential therapeutic vulnerabilities associated with PTEN loss in FN-RMS.

Main Methods:

• Utilized a genetically engineered mouse model of FN-RMS with Pten deletion.
• Analyzed tumor differentiation status, gene expression profiles, and signaling pathway activation (PI3K/mTOR).
• Investigated the role of transcription factors, specifically Pax7, in mediating Pten loss phenotypes through genetic deletion experiments.

Main Results:

• Pten deletion in FN-RMS models led to less differentiated tumors resembling human embryonal RMS.
• PTEN loss activated the PI3K pathway but not mTOR; nuclear PTEN function loss was implicated.
• Pten deletion increased expression of neural and skeletal muscle transcription factors, including Pax7, and Pax7 deletion rescued Pten loss phenotypes, inducing smooth muscle differentiation.

Conclusions:

• PTEN loss in FN-RMS is linked to a PAX7 lineage-specific transcriptional program.
• Tumor identity in Pten-deficient FN-RMS becomes dependent on PAX7, presenting a synthetic essentiality.
• Targeting PAX7 may represent a novel therapeutic strategy for PTEN-altered FN-RMS.