Interplay of fusion genes and cellular context in sarcoma

Recurrent chromosomal translocations that result in fusion proteins are well-established oncogenic drivers. Cancers carrying fusion genes typically exhibit few other somatic mutations, supporting that fusion proteins are potent oncogenes. This is the case for many soft tissue sarcomas. Indeed, our experience with fusion protein-driven pediatric sarcomas suggests that Knudsons classical two-hit hypothesis of cancer initiation may take the unusual form of a single oncogenic fusion gene hitting a susceptible epigenetic / developmental cell-of-origin, without requiring any further genetic events. Importantly, and in contrast to most other genetic aberrations, fusion genes tend to be highly cancer- specific and are pathognomic for (i.e., define) the malignancy in which they occur. The fact that many fusion driven cancers occur in children and young adults further supports the notion that factors related to developmental timing may be associated with fusion-gene driven oncogenesis. Many oncogenic fusion proteins promote tumor development specifically in the context of stem and progenitor cell populations, while the ectopic expression of the fusion oncogene in other cell types often leads to cell death or to fusion gene silencing. Moreover, they have the capacity to block differentiation in these cells by hijacking the transcriptional regulatory machinery (e.g., by repression of cell differentiation programs). It appears that it takes the right fusion oncogene in the right cell type and developmental stage to induce fusion- driven cancer types, while other combinations of fusion genes, cellular lineage and developmental stage are either not tolerated or are insufficient to achieve full transformation. This project tackles a fundamental question in cancer biology: Why and how do certain oncogenic driver genes promote cancer in one cellular context but not in another. We focus on fusion oncogenes relevant to sarcoma. By combining pluripotent stem cell differentiation with forced expression of fusions, single- cell analysis, and functional perturbation experiments, we will systematically probe the cellular contexts and molecular mechanisms of fusion-driven sarcomagenesis in human cells. More specifically this project seeks to reveal: i. What makes a particular cell state permissive to the activity of a specific fusion oncogene; ii. What is the shared and cell-type-specific effect of fusion oncogenes when expressed in different cell types; iii. If a permissive cellular context is sufficient for fusion oncogenes to execute their tumorigenic programs. A systematic analysis of the molecular response of a particular cellular context to different fusion oncogenes will not only lead to new molecular insights into fusion-driven carcinogenesis but could also help identify cell context-specific therapeutic vulnerabilities.