Abstract IA03: Insights into the origins and pathogenesis of embryonal rhabdomyosarcoma
Authors: Drummond Catherine J. , Devine Daniel , Garcia Matthew R. , Hatley Mark E. 
Published: May 2016

Abstract
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 is an aggressive skeletal muscle-lineage tumor composed of malignant myoblasts that fail to exit the cell cycle and are blocked from fusing into syncytial muscle. RMS includes two histolopathologic 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 drives only ERMS neoplasia. We illustrated that the transcriptome 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. Lineage tracing the aP2-Cre with reporter mice illustrated aP2-Cre expression in both brown and white adipose tissue as well as a discrete population of cells lying between skeletal muscle fibers but not beneath the laminin sheath of the muscle fibers. These aP2-lineage cells are distinct from Pax7-positive skeletal muscle stem cells or satellite cells. The aP2-lineage cells do not contribute to myotube formation in vitro. When compared to aP2-Cre;R26-Tom mice, the addition of oncogenic SmoM2 (aP2-Cre;R26-Tom;SmoM2) results in embryonic expansion of the aP2-lineage interstitial muscle cells. Our findings suggest that non-skeletal muscle progenitors are a potential cell of origin for Sonic Hedgehog-driven ERMS.
Citation Format: Catherine J. Drummond, Daniel Devine, Matthew R. Garcia, Mark E. Hatley. Insights into the origins and pathogenesis of embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA03.