Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes.

Deborah Morena,Javed Khan,Gabriella Sozzi,Paolo Provero,Alessandro Morotti,Silvia Miretti,Tiziana Crepaldi,Carola Ponzetto,Nicola Maestro,Francesca Bersani,Roberto Chiarle,Valentina Foglizzo,Petar Šćepanović,Patrizia Gasparini,Marcello Francesco Lingua,Michela Casanova,Andrea Ferrari,Valentina Sala,Riccardo Taulli,Ugo Ala,Paolo E Forni ,Jack F Shern

doi:10.7554/elife.12116

Abstract

Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity.

Highlights

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, is a rare but aggressive malignancy (Hawkins et al, 2013; Saab et al, 2011)
At variance with other sarcoma subtypes, a satellite cell-like signature is considered a hallmark of Embryonal Rhabdomyosarcoma (ERMS) (Hatley et al, 2012; Rubin et al, 2011) while the complete absence of tissue-specific markers in undifferentiated pleomorphic sarcoma (UPS) suggests an origin from early mesenchymal precursors
In a Pax7 wild type background, where satellite cells are present in normal number, Hepatocyte Growth Factor (HGF) induction prevalently resulted in ERMS formation with only less than 10% of mice developing UPS

Summary

Introduction

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, is a rare but aggressive malignancy (Hawkins et al, 2013; Saab et al, 2011). Cell biology Developmental biology and stem cells eLife digest Soft tissue sarcomas are rare cancers that originate in tissues such as muscles, tendons, cartilage and fat. These cancers are further classified into subtypes based on their appearance. Recent experiments have suggested that these subtypes appear different, they may both arise from the cells that build muscles.

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