Abstract 1036: Non-myogenic origin of embryonal rhabdomyosarcoma
Authors: Drummond Catherine J. , Garcia Matthew R. , Devine Daniel J. , Peters Jennifer , Frohlich Victoria , Finkelstein David , Hatley Mark E. 
Published: July 2017

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS includes two histopathologic subtypes: alveolar RMS, driven by the fusion protein PAX3/7-FOXO1, and embryonal RMS (ERMS), which is genetically heterogeneous. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle such as the prostate, bladder, biliary tree and the omentum. Previously, we showed that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of an adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human ERMS. In this model, tumorigenesis occurs with high penetrance (~80%), is early onset (by 2 months of age), and is restricted to the head and neck. Also, unlike previous RMS models, this model requires no additional background mutations, such as inactivation of p53, and results in only ERMS neoplasia. We illustrated that the gene expression signature of the aP2-Cre;SmoM2 tumors recapitulates both other mouse ERMS models as well as human ERMS. With the short latency and anatomic restricted tumor location, we sought to leverage this model to explore the cell of origin. Here, we use genetic fate mapping of aP2-cre with reporter mice to determine the effect of constitutive hedgehog activation on the identity and localization of aP2-Cre expressing cells. aP2-cre expressing cells are found in both brown and white adipose and to be localized within the muscle intersitium but not beneath the laminin sheath of the muscle fibers. These aP2-cre expressing cells are distinct from Pax7-positive skeletal muscle stem cells or satellite cells and do not contribute to myofiber formation. Instead these cells were confirmed to be endothelial by gene expression analysis. Colocalization between aP2-cre expressing cells and CD31 was also observed. When compared to aP2-Cre;R26-Tom mice, the addition of oncogenic SmoM2 (aP2-Cre;R26-Tom;SmoM2) resulted in embryonic expansion of these aP2-lineage interstitial muscle cells and formation of ERMS. Our findings suggest that non-skeletal muscle progenitors are a cell of origin for Sonic Hedgehog-driven ERMS.

Citation Format: Catherine J. Drummond, Matthew R. Garcia, Daniel J. Devine, Jennifer Peters, Victoria Frohlich, David Finkelstein, Mark E. Hatley. Non-myogenic origin of embryonal rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2017-1036