1. Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors
- Author
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Danwei Huangfu, Brigita Meskauskaite, Yun-Shao Sung, Lei Zhang, Maria Jasin, Fabio Vanoli, William Mallen, Laurie Herviou, Yumi Fujisawa, Cristina R. Antonescu, and Steven Simon
- Subjects
0301 basic medicine ,Cancer Research ,sarcoma ,Oncogene Proteins, Fusion ,Human Embryonic Stem Cells ,Context (language use) ,hES cells ,Histiocytoma, Malignant Fibrous ,Biology ,medicine.disease_cause ,Article ,Cell Line ,Fusion gene ,03 medical and health sciences ,0302 clinical medicine ,ATF1 ,hES-MP cells ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,clear cell sarcoma ,Progenitor cell ,Molecular Biology ,Transcription factor ,Gene Expression Profiling ,Mesenchymal stem cell ,Embryonic stem cell ,Cell biology ,Cell Transformation, Neoplastic ,030104 developmental biology ,Gene Expression Regulation ,EWSR1 ,030220 oncology & carcinogenesis ,angiomatoid fibrous histiocytoma ,Mutation ,CREB1 ,CRISPR-Cas9 ,Tumor Suppressor Protein p53 ,Transcriptome ,Carcinogenesis ,Signal Transduction - Abstract
Chromosomal translocations constitute driver mutations in solid tumors and leukemias. The mechanisms of how related or even identical gene fusions drive the pathogenesis of various tumor types remain elusive. One remarkable example is the presence of EWSR1 fusions with CREB1 and ATF1, members of the CREB family of transcription factors, in a variety of sarcomas, carcinomas and mesotheliomas. To address this, we have developed in vitro models of oncogenic fusions, in particular, EWSR1-CREB1 and EWSR1-ATF1, in human embryonic stem (hES) cells, which are capable of multipotent differentiation, using CRISPR-Cas9 technology and HDR together with conditional fusion gene expression that allows investigation into the early steps of cellular transformation. We show that expression of EWSR1-CREB1/ATF1 fusion in hES cells recapitulates the core gene signatures, respectively, of angiomatoid fibrous histiocytoma (AFH) and gastrointestinal clear cell sarcoma (GI-CCS), although both fusions lead to cell lethality. Conversely, expression of the fusions in hES cells differentiated to mesenchymal progenitors is compatible with prolonged viability while maintaining the core gene signatures. Moreover, in the context of a mesenchymal lineage, the proliferation of cells expressing the EWSR1-CREB1 fusion is further extended by deletion of the tumor suppressor TP53. We expect the generation of isogenic lines carrying oncogenic fusions in various cell lineages to expand our general understanding of how those single genetic events drive tumorigenesis while providing valuable resources for drug discovery.
- Published
- 2021