Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a highly malignant tumor that is histologically related to skeletal muscle, yet genetic and molecular lesions underlying its genesis and progression remain largely unknown. In this study we have compared the molecular profiles of two different mouse models of RMS, each associated with a defined primary genetic defect known to play a role in rhabdomyosarcomagenesis in man. We report that RMS of heterozygous Patched1 (Ptch1) mice show less aggressive growth and a greater degree of differentiation than RMS of heterozygous p53 mice. By means of cDNA microarray analysis we demonstrate that RMS in Ptch1 mutants predominantly express a number of myogenic markers, including myogenic differentiation 1, myosin heavy chain, actin, troponin and tropomyosin, as well as genes associated with Hedgehog/Patched signaling like insulin-like growth factor 2, forkhead box gene Foxf1 and the growth arrest and DNA-damage-inducible gene Gadd45a. In sharp contrast, RMS in p53 mutants display higher expression levels of cell cycle-associated genes like cyclin B1, cyclindependent kinase 4 and the proliferation marker Ki-67. These results demonstrate that different causative mutations lead to distinct gene expression profiles in RMS, which appear to reflect their different biological characteristics. Our results provide a first step towards a molecular classification of different forms of RMS. If the described differences can be confirmed in human RMS our results will contribute to a new molecular taxonomy of this cancer, which will be critical for gene mutation-and expression-specific therapy.

Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma

“…First, Ptch heterozygous mice, which develop embryonal subtype-like RMS (Hahn et al, 1998;Kappler et al, 2004), likely present a suitable model for the pre-clinical evaluation of Hh antagonists, as the gene expression pattern of Hh signaling and myogenic markers identified in this study in ERMS and fusion gene-negative ARMS is similar to the profile that we previously described in Ptch heterozygous mice (Kappler et al, 2004;AZ and HH, unpublished data). Second, our study identifies specific subgroups of RMS that harbor constitutive Hh activation, which may occur in a cell-intrinsic manner, implying that they are prime candidates for future studies with small molecule inhibitors of the Hh pathway.…”

Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling

“…Growth arrest and DNA-damage-inducible 45 a (Gadd45a) is elevated in rhabdomyosarcoma and medulloblastoma arising in Patched þ /Àmice (Kappler et al, 2004a, b). However, it remains unclear whether this gene is transcriptionally regulated by the Hedgehog pathway, or if the upregulation simply reflects observed changes in Trp53 expression in the tumours, as Gadd45a is associated with p53-mediated cell cycle arrest (Amundson et al, 1998).…”

Protecting the hedgerow: p53 and Hedgehog pathway interactions

“…19 Similarly, constitutive activation of Hh signalling in mice, by the removal of one Ptch1 allele can induce formation of basal cell carcinoma and medulloblastoma. Expression of an activated form of Smo or Gli2 in mice has also been demonstrated to have tumorigenic potential, such that tissue specific expression in skin results in the…”