Hedgehog Signaling: A Therapeutic Target in Embryonal Rhabdomyosarcoma?

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, occurs in two major histological subtypes, embryonal (ERMS) and alveolar (ARMS).

Aberrant Hedgehog (Hh) signalling due to germline mutations in the Hh receptor Patched (Ptch) has been linked to ERMS. Our goal is to better understand the role of this pathway in the pathogenesis of RMS, and to test it as a therapeutic target.

Sixty per-cent of heterozygous Ptch mutant mice develop RMS resembling the human embryonal subtype. ERMS formation is accompanied by the silencing of the wild-type Ptch allele. Consistently, the formation of ERMS can be prevented by treating mice with the DNA methyltransferase inhibitor 5-aza-2'deoxycytidine in combination with the histone deacetylase inhibitor valproic acid. No ERMS are observed after mono- or biallelic postnatal deletion of Ptch, suggesting that they are initiated exclusively before birth. This is consistent with our preliminary data indicating that ERMS origin from a prenatal cell type contributing to skeletal muscle development.

ERMS of Ptch mutants show excessive Hh signalling activity. Cyclopamine is the prototype of Hh pathway inhibitors and exert anti-cancer activity in other tumor entities associated with Ptch mutations. Cyclopamine suppresses the activity of Hh pathway in clinically overt murine ERMS, but it has no effect on tumor progression. This is in contrast to the effects of doxorubicin. This suggests that ERMS may originally depend on Hh signaling during the initiation process, but become independent from this signaling pathway when tumors progress. Taken together, Ptch knockouts provide a useful system to investigate biology of ERMS and to optimize its treatment.