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Preclinical Models & Translational Research

(P 257) CHARACTERIZING THE EVOLUTION AND THERAPEUTIC RESPONSE OF UNDIFFERENTIATED PLEOMORPHIC SARCOMAS USING MOUSE MODELS

Location: The Liffey, Level 1
Objective: Undifferentiated pleomorphic sarcomas (UPS) are aggressive sarcomas with few effective treatment options. Because of the rarity of these sarcomas and the paucity of representative disease models, little is known about how they develop and respond to therapeutics. The goal of our study is to identify cell state trajectories that define sarcomagenesis and to identify essential molecular features of UPS in response to chemotherapy.

Methods: We used single cell transcriptomics to study the initiation and evolution of UPS in an autochthonous genetically engineered mouse model. We profiled tumor development at multiple time points and computationally defined key cell state transitions during sarcomagenesis and during therapy response.

Results: Interestingly, we identify two discrete evolutionary pathways that arise in parallel in the mouse model. To determine how these discrete lineages evolve, we used barcoded lentiviruses to initiate tumor development in the mouse model. By assessing the population of barcoded lentiviruses within the different transcriptional lineages, we determined there likely exists one or more cells of origin that define different UPS cell states. In addition, by perturbing these cell states with chemotherapy and comparing them to similar treatment in patient-derived xenografts, we uncovered core UPS cell states reflecting the response to chemotherapeutic pressure.

Conclusion: At least two major transcriptional subpopulations develop in parallel in a GEMM of UPS, with differing essential molecular features and potentially cells of origin. The intermediary cell states leading to these divergent transcriptomic populations may represent entry points for future therapeutic strategies. In addition, we identify cell states that enrich after chemotherapeutic in PDX models that mimic those that arise in the GEMM model, providing further insight into the human relevance of the GEMM model of UPS.