Abstract 97: Mechanisms of action and regulation of the progranulin/EphA2 axis in mesothelioma

Abstract

Abstract Mesothelioma is an aggressive tumor with very poor prognosis. The limited availability of therapeutic options for mesothelioma patients suggests the need for a better understanding of mesothelioma biology and the identification of novel therapeutic targets. Progranulin is a pluripotent growth factor whose dysregulation is implicated in several human pathologies including cancer. The pro-tumorigenic activity of progranulin depends on the activation of its functional receptor EphA2. Indeed, in bladder cancer, progranulin promotes EphA2 phosphorylation at Ser897 and triggers EphA2 oncogenic action resulting in increased tumor cell migration, invasion and in vivo tumor growth. Both progranulin and EphA2 are expressed in mesothelioma, with progranulin promoting tumor angiogenesis in a VEGF-independent manner and EphA2 being often mutated or overexpressed. However, in mesothelioma, the potential functional interaction between progranulin and EphA2 is unexplored. Using a panel of mesothelioma cell lines covering all mesothelioma subtypes, we observed increased levels of phosphorylated EphA2 at Ser897 when compared to immortalized normal mesothelial cells, and the levels of phosphorylation positively correlated with progranulin expression. Progranulin-dependent activation of EphA2 in mesothelioma cells promoted the activation of the MAPK and AKT pathways and ERK1/2-dependent EphA2 phosphorylation at Ser897. Transient depletion of progranulin by siRNA approaches as well as GRN gene knock-out by CRISP/Cas9 strategies in mesothelioma cells reduced the activation of the AKT signaling pathway and inhibited the migratory and invasive capabilities of progranulin-depleted cells when compared to parental cells, suggesting that the progranulin/EphA2 axis is oncogenic in mesothelioma. However, EphA2 genetic ablation resulted in an increased basal activation of AKT and MAPK and in progranulin-evoked EphA2-independet AKT/MAPK activation, indicating that alternative membrane receptors might compensate for EphA2 loss and sustain progranulin action in mesothelioma. Using several pharmacological and genetic approaches, we uncovered a role for EGFR and FAK in compensating for EphA2 loss by triggering progranulin-dependent oncogenic signaling in mesothelioma, highlighting a complex functional cross-talk between EphA2, EGFR and FAK in mediating progranulin-dependent tumorigenesis. Thus, these results suggest the need for combinatorial therapeutic approaches to blunt progranulin oncogenic action in mesothelioma. Citation Format: Elisa Ventura, Simone Buraschi, Stephen J. Williams, Antonino Belfiore, Renato V. Iozzo, Antonio Giordano, Andrea Morrione. Mechanisms of action and regulation of the progranulin/EphA2 axis in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 97.