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.
Highlights
Phosphatase and Tensin Homolog (PTEN) promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS)
The nearly universal PTEN promoter hypermethylation in FNRMS6 led us to investigate whether Pten loss is sufficient to drive rhabdomyosarcomagenesis by conditionally deleting a Ptenflox allele with Cre recombinase expressed from the adipose protein 2 promoter (Supplementary Fig. 1a)[22]
The cell of origin and genetic perturbations cooperate in tumor cell transformation and fate determination highlighting cellular and developmental pliancy in tumorigenesis
Summary
PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Pax[7] deletion completely rescued the effects of Pten loss These Pten;Pax[7] 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. Increasing evidence suggests PTEN maintains a myriad of tumor-suppressive functions aside from negatively regulating the PI3K pathway[11]. In contrast to modulating the PI3K/AKT/mTOR pathway, we reveal PTEN loss drives a transcriptional axis centered on PAX7 necessary for FN-RMS tumor identity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
