(P 380) INVESTIGATING THE ROLE OF HISTONE DEACETYLASE-3 IN METASTATIC UNDIFFERENTIATED PLEOMORPHIC SARCOMA

Objective: Undifferentiated Pleomorphic Sarcoma (UPS) is among the most commonly diagnosed soft tissue sarcoma in adults and carries a poor prognosis for patients with metastatic disease. There are no therapeutic options for metastatic UPS and robust heterogeneity within the primary tumors negatively impacts treatment efficacy. How the diverse populations contribute to tumor growth and metastasis is poorly understood. Previous literature identifies histone deacetylases as drivers of metastasis. My objective is to identify and elucidate the epigenetic mechanisms of histone deacetylase-3 (HDAC3) in metastatic UPS.

Methods: Our models utilize a localized cre-activation system, generating primary tumors that harbor an oncogenic KrasG12D mutation and p53 knockout. Investigation of clonal dynamics in UPS was achieved by incorporating CRISPR barcoding and fluorescent reporters into our models. Following tumor initiation, amputation of the tumor bearing limb is performed and metastasis is observed overtime. Subsequent in vitro assays and tumor studies utilize primary cell cultures harvested from these mouse models.

Results: Tumors generated in our models recapitulate the clonal heterogeneity, characteristic of UPS. Excitingly, lung metastasis was shown to arise from a single clone. This specific population, which can migrate and form lung tumors, we termed metastatic initiating cells (MCs). Comparative analysis of the MC and the non-metastatic initiating cells (nMCs) revealed distinct expression clusters despite insignificant differences in transcriptomic and mutational profiles. Investigating regulators of gene expression identified HDACs, specifically HDAC3, to play a key role in the ability of the MC population to successfully colonize the lung.

Conclusion: We have demonstrated the monoclonal origin of UPS metastasis using murine models. My data highlights a key regulatory role of HDAC3 in the metastatic potential of the MC population. Loss of Hdac3 in vivo significantly impaired migrative and invasive properties and delayed primary tumor growth. My findings have the potential to elucidate an ill-defined mechanism of UPS pathogenesis and propose and targeted approach for therapeutic intervention. Ongoing studies aim to understand the functional significance of Hdac3 in the MC population and the underlying mechanism through which Hdac3 regulates metastasis in UPS.