Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes.
Deborah MorenaNicola MaestroFrancesca BersaniPaolo Emanuele ForniMarcello Francesco LinguaValentina FoglizzoPetar ŠćepanovićSilvia MirettiAlessandro MorottiJack F ShernJaved KhanUgo AlaPaolo ProveroValentina SalaTiziana CrepaldiPatrizia GaspariniMichela CasanovaAndrea FerrariGabriella SozziRoberto ChiarleCarola PonzettoRiccardo TaulliPublished in: eLife (2016)
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.
Keyphrases
- growth factor
- induced apoptosis
- single cell
- combination therapy
- cell cycle arrest
- stem cells
- wild type
- clinical trial
- risk factors
- gene expression
- endoplasmic reticulum stress
- cell therapy
- machine learning
- electronic health record
- cell death
- epithelial mesenchymal transition
- liver injury
- genome wide
- smoking cessation