Abstract 3457: A possible role for the Hedgehog pathway ligands Desert and Indian in rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children, is thought to derive from embryonic cells committed to developing into skeletal muscle and is divided into 2 major subtypes: embryonal and alveolar (eRMS and aRMS, respectively). Hedgehog pathway-belonging proteins are considered to be key regulators of development in pluricellular organisms, exerting crucial roles in processes such as tissue patterning, proliferation and differentiation. Likewise, Hedgehog (HH) signaling also plays important roles in adult organisms such as stem cell maintenance or tissue repair. The 3 Hedgehog ligands present in mammals are named Sonic (SHH), Indian (IHH) and Desert (DHH). Upon binding of a Hedgehog ligand to Patched, active SMO is detected in the membrane and prevents GLI proteosomal processing. GLI is then translocated to the nucleus where it binds to and regulates GLI-specific promoters. Despite the knowledge gathered to date, the mechanism that drives activation of the pathway in RMS is not well understood; the relative importance of the 3 HH ligands has not been elucidated and a possible role for Desert or Indian HH in the pathogenesis of RMS has not been studied. Previous works reported undetectable levels of SHH in RMS tumors and cell lines with Hedgehog pathway activation, suggesting a mechanism of GLI1-upregulation independent of autocrine SHH expression. Herein, we report extremely low levels of SHH expression in the majority of RMS patients (approximately 70%). Conversely, we report a prominent expression of Desert and Indian HH ligands - instead of SHH - in RMS, thereby supporting the possible existence of an autocrine ligand-dependent activation of the Hedgehog pathway in this neoplasia. Furthermore, the expression of DHH significantly correlates with GLI1 levels, pointing to a crucial role of this ligand for the activation of the pathway in RMS. Citation Format: Josep Roma, Anna Almazán-Moga, Pablo Velasco, Carla Molist, Vidal Isaac, Miguel F. Segura, Aroa Soriano, Jubierre Luz, Paris Laia, Reventós Jaume, José Sánchez de Toledo, Soledad Gallego. A possible role for the Hedgehog pathway ligands Desert and Indian in rhabdomyosarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3457. doi:10.1158/1538-7445.AM2014-3457