(P 394) IDENTIFYING THE INTERACTOME OF THE ONCOGENIC FUSIONS OF SARCOMAS TO REVEAL NOVEL THERAPEUTIC TARGETS

Objective: Sarcomas are rare and heterogeneous malignant mesenchymal tumors, characterized by distinct biology and clinical behavior. Over the past decade, a molecular classification has defined sarcomas based on their genetic aberrations. Around 30% of sarcomas carry oncogenic fusions as their essential tumorigenic feature. The resulting chimeric proteins lack proper regulatory domains, leading to inappropriate functional roles. Additionally, chimeras interfere with signaling, genetic, and epigenetic modalities, influencing the transcriptional landscape. To date, persistent challenges remain to define potential therapeutic targets within their oncogenic nodes. Consequently, sarcomas become diagnosed and classified partly based on their gene fusions. Each histological subtype is associated with a distinct set of fusions unique to that subtype. The corresponding chimeric proteins trigger the aberrant growth of a particular subtype through epigenetic deregulations, mediating in turn, differential gene expression (Epi/DGE). They orchestrate the subtype-specific Epi/DGE pattern via protein-protein interaction (PPI) networks. The interactome of chimeric proteins intervenes in signal transduction and regulation of the subtype-specific Epi/DGE.

We HYPOTHESIZE that the chimeric proteins, specific to each histological subtype, share common interactors to exert this function.
Our OBJECTIVE is to characterize the common interactors for the fusions of each histological subtype and validate the interactome-mediated Epi/DGE regulations in fusion-driven sarcomas.

Methods: For this aim, the oncogenic fusion genes have been designed and cloned (122 fusions) to be ectopically expressed in relevant cell models. This will allow us to study by functional assays the tumorigenic activity of the chimeras (transformation, proliferation, migration and invasion). the complexes of chimeric proteins, along with their interacting partners, will be characterized using Tandem Affinity Purification/Mass Spectrometry (TAP/MS).

Results: Transcriptomic and proteomics analysis will be performed to understand the oncogenic fusion-mediated Epi/DGE. The interactome and the transcriptome of chimeric proteins will be biologically validated using human sarcoma tissues sourced from the sarcoma bank of data and biological material of the CIUSSS of the Est of Montreal.

Conclusion: Our approach will enable the identification of potential therapeutic targets at the protein level, providing insights for more effective treatments that specifically target the molecular characteristics of each sarcoma subtype.