Essential role of PLD2 in hypoxia-induced stemness and therapy resistance in ovarian tumors

Abstract

Hypoxia in solid tumors is a source of chemoresistance that determines poor patient prognosis and relies on the presence of cancer stem cells (CSCs). Here we use ovarian cancer (OC) as a model and a combination of 2D and 3D cell cultures, xenograft models, patient samples, transcriptional databases, iPSCs and ATAC-seq, to address the mechanisms leading to hypoxia-induced CSC generation and chemoresistance. We show that hypoxia activates the expression of the PLD2 gene encoding phospholipase D2. PLD2 overexpression leads to increased CSC-like features, similar to hypoxia, while PLD2 depletion in hypoxia partially suppresses these effects, indicating a role of PLD2 in hypoxia-induced CSC generation in OC. Finally, PLD2 overexpression provokes chemoresistance that is suppressed by combination treatment with PLD2 inhibition. Altogether, our work highlights the HIF-1D-PLD2 axis in hypoxia-induced CSC generation and chemoresistance in OC and proposes an alternative treatment for patients with high PLD2 expression. Statement of SignificanceHypoxia in solid tumors is a major source of chemoresistance and cancer stem cells. We show that hypoxia-induced stemness is mediated by phospholipase D2 in ovarian tumors, generating therapy resistance that is overcome by phospholipase D inhibition. Therefore, we propose an alternative treatment for patients with high PLD2 expression.