Unraveling the molecular basis of the metastatic process in Ewing sarcoma: insights into the role of LOXHD1 and PARP14

Abstract

[eng] HYPOTHESIS AND OBJECTIVES: 1. Hypothesis: Metastasis is the worst prognostic factor in EwS patients, dropping patients’ overall survival to less than 30 %43. Further, about 25 % of patients present with metastatic disease at diagnosis13,27. Scarce knowledge about the molecular mechanisms that regulate the metastatic process is the main reason behind the lack of clinical therapeutic efficacy in patients in this stage of the disease. Recent transcriptomic analyses performed by the Sarcoma Research Group (IDIBELL, Barcelona, Spain) report LOXHD1 and PARP14 as being upregulated in metastases compared to paired tumors, claiming for a possible role of these proteins in EwS disease progression. Other studies have also highlighted the role of LOXHD1 in EwS metastasis189,190. Additionally, PARP14 has been found to be involved in tumorigenesis, TME and metastasis in other solid malignancies199,227,256,259. Therefore, we propose the hypothesis that LOXHD1 and PARP14 may act as key regulators of EwS disease progression, impacting on the metastatic potential of this pediatric cancer and inducing specific vulnerabilities that could be exploited for the treatment of these young patients.

2. Objectives: The main objectives of this doctoral thesis are: I. Characterize LOXHD1 and PARP14 expression in EwS tumors, metastases and cells. II. Elucidate LOXHD1 and PARP14 role in sustaining EwS metastatic spreading by loss and gain of function assays in vitro and in vivo. III. Explore the molecular mechanisms underlying PARP14 pro-metastatic function in EwS