Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program. We used microarrays to detail the global program of gene expression in mouse mesenchymal chondrosarcoma
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program.
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors (eSZ) followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression in eSZ cells successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation. Chromatin immunoprecipitation sequencing analyses indicated frequent association between HEY1-NCOA2-binding peaks and active enhancers. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. Whereas Runx2 knockout resulted in significant delay in tumor onset, aggressive growth of immature small round cells was induced. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth both in vitro and in vivo, abrogating expression of genes downstream of HEY1-NCOA2 and Runx2. Thus, HEY1-NCOA2 expression induces malignant transformation by modulating the transcriptional program in chondrogenic differentiation.
