RESUMEN
Epigenetic alterations, including DNA methylation and post translational modifications to histones, drive tumorigenesis and metastatic progression. In the context of bone metastasis, epigenetic modifications in tumor cells can modulate dissemination of cancer cells to the bone, tumor progression in the bone marrow, and may be associated with patient survival rates. Bone disseminated tumor cells may enter a dormant state or stimulate osteolysis through the "vicious cycle" of bone metastasis where bone disseminated tumor cells disrupt the bone microenvironment, which fuels tumor progression. Epigenetic alterations may either exacerbate or abrogate the vicious cycle by regulating tumor suppressors and oncogenes, which alter proliferation of bone-metastatic cancer cells. This review focuses on the specific epigenetic alterations that regulate bone metastasis, including DNA methylation, histone methylation, and histone acetylation. Here, we summarize key findings from researchers identifying epigenetic changes that drive tumor progression in the bone, along with pre-clinical and clinical studies investigating the utility of targeting aberrant epigenetic alterations to treat bone metastatic cancer.
RESUMEN
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.