Dataset Information

Exosomes derived from mouse myoblasts expressing PAX3-FOXO1 oncogene protect recipient cells from oxidative stress and promote plasticity

ABSTRACT: Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Mass spectrometry analysis of the protein cargo of exosomes isolated from C2C12 myoblasts transduced with P3F fusion gene revealed 52 deregulated proteins compared to control cells, with 26 enriched and 26 depleted proteins. Using both PANTHER gene classification and IPA software, we found that the main biological processes in which the 52 deregulated proteins are involved include “Catalytic activity”, “Binding”, “Metabolic process” and “Cellular process”. The pathways engaging the 26 enriched proteins include “14-3-3 mediated signaling”, “Cell cycle” and “ERK5, VEGF, IGF1and p70S6K signaling”. Main nodes in which deregulated exosome protein and miRNA intersected revealed pathways conferring protection from stress and promoting plasticity. Physiologically, exosomes derived from P3F-C2C12 cells activated ERK, 4-EBP1 and MMP-2, factors known to increase cell proliferation and invasion. In addition, they increased angiogenesis as evidenced by studies on HUVEC cells, and promoted stemness of MEFs and C2C12 cells. Treating stromal cells with exosomes from P3F-C2C12 cells protected them against effects of hydrogen peroxide (H2O2) in vitro, noting that P3F-C2C12 cells produce less ROS and are more resistant to induced exogenous oxidative stress as compared to control cells. Our findings highlight the role of P3F fusion protein in modulating exosome cargo to confer a protective effect on recipient cells against oxidative stress and promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of ARMS.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Myoblast

SUBMITTER: Wenjing Peng

LAB HEAD: Yehia Mechref

PROVIDER: PXD017543 | Pride | 2021-09-08

REPOSITORIES: Pride

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Publications

Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity.

Fahs Assil A Ramadan Farah F Ghamloush Farah F Ayoub Abeer J AJ Ahmad Fatima Ali FA Kobeissy Firas F Mechref Yehia Y Zhao Jingfu J Zhu Rui R Hussein Nader N Saab Raya R Ghayad Sandra E SE

Frontiers in oncology 20201001

Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Advanced ...[more]

PMID: 33117671

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Dataset Information

Exosomes derived from mouse myoblasts expressing PAX3-FOXO1 oncogene protect recipient cells from oxidative stress and promote plasticity

Publications

Effects of the Oncoprotein PAX3-FOXO1 on Modulation of Exosomes Function and Protein Content: Implications on Oxidative Stress Protection and Enhanced Plasticity.

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