Investigating mechanistic roles of a novel oncofusion-driven transcript isoform in Ewing sarcoma
Ewing sarcoma (EwS) is a bone cancer that primarily impacts children, adolescents and young adults. This disease is defined by a genetic modification, called an EWS-FLI1 gene fusion, that resultsin production of a new protein that is a fusion of two proteinsthat are normally found separately within human cells. Thisfusion protein resultsin a dramatic shift in how cells behave by rewiring how other proteins are produced, resulting in EwS. Asthisfusion isthe primary event that supportsthe formation of EwS, there is a critical need to understand exactly how it affects cellsto design effective waysto treat this disease. In the past, many research groups have decoded the identities of proteins whose production is modified by cancer-promoting fusion, many of which are only observed in EwS. A critical goal of EwS research isto identify which of these proteins are important for tumor formation and progression, and whose disruption may be therapeutically relevant in the treatment of this disease. For many of these proteinsthat are uniquely observed in EwS, thisis often challenging due to a lack of knowledge about these specific protein forms and how they interact with one another in the unique cellular environment created by the fusion. However, their specificity to EwS and linksto the fusion make these unique protein products attractive targetsfor study due to their potential to impact our understanding of this disease and to reveal new targetsfor therapy.
Project Goal:
In preliminary work leading up to this project, we compiled information from multiple other studiesthat investigated how EwS cells change in response to the production of the characteristic EwS fusion protein, called EWS-FLI1. This analysisled usto unexpectedly identify a new,shortened version of a protein called DLG2, whose production we observed to be highly specific to EwS compared to other cancers or normal cells. Although the normal form of DLG2 has been the subject of limited studiesin the context of cancer, current data suggest that it may support functionsthat suppresstumor formation and istherefore not produced in most cancer types. However, the shortened version of DLG2 produced in EwS cells(called DLG2?3) lacks most of the components attributed with these tumor-suppressive functions, and has not yet been described in the context of EwS or cancer in general. Our most recent work suggeststhat EwS cells depend on DLG2?3 to support cell function, but the mechanismsthat underpin how remain unclear. We hypothesize that the shortened form of DLG2 possesses a function that EwS cells depend on to support tumor formation. In this project, we will use a combination of approachesto define exactly how DLG2?3 operates within EwS cells, with the goal of identifying new waysto disrupt these pathwaysin order to block the tumor-promoting abilities of EwS cells.
