PARP inhibitors promote stromal fibroblast activation by enhancing CCL5 autocrine signaling in ovarian cancer

Abstract

Cancer-associated fibroblasts (CAFs) play significant roles in drug resistance through different ways. Antitumor therapies, including molecular targeted interventions, not only effect tumor cells but also modulate the phenotype and characteristics of CAFs, which can in turn blunt the therapeutic response. Little is known about how stromal fibroblasts respond to poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian cancer (OC) and subsequent effects on tumor cells. This is a study to evaluate how CAFs react to PARPis and their potential influence on PARPi resistance in OC. We discovered that OC stromal fibroblasts exhibited intrinsic resistance to PARPis and were further activated after the administration of PARPis. PARPi-challenged fibroblasts displayed a specific secretory profile characterized by increased secretion of CCL5, MIP-3α, MCP3, CCL11, and ENA-78. Mechanistically, increased secretion of CCL5 through activation of the NF-κB signaling pathway was required for PARPi-induced stromal fibroblast activation in an autocrine manner. Moreover, neutralizing CCL5 partly reversed PARPi-induced fibroblast activation and boosted the tumor inhibitory effect of PARPis in both BRCA1/2-mutant and BRCA1/2-wild type xenograft models. Our study revealed that PARPis could maintain and improve stromal fibroblast activation involving CCL5 autocrine upregulation. Targeting CCL5 might offer a new treatment modality in overcoming the reality of PARPi resistance in OC.

Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer

“…Moreover, in the CRISPR- Cas9 competition assay cells are analyzed shortly after gRNA transfection allowing them no time to adapt to the loss of the target gene, which can happen by gene downregulation assays using shRNA or classical gene knockout experiments using CRISPR- Cas9 which may also face the problem on clonal effects. In addition, we cannot rule out the possibility that the genetic loss of a single gene in an in vivo scenario alters the cell response to PARPi, either by interference with the tumor microenvironment or triggering immune response as pointed out by recent publications [ 65 – 68 ].…”

Secretome Analysis of Rabbit and Human Mesenchymal Stem and Endothelial Progenitor Cells: A Comparative Study

“…Here, we used a human cytokine array to detect cytokines presented in the conditioned media of rabbit and human stem/progenitor cells. This array has already been successfully used in several human studies [8,[20][21][22], but also in rabbit study [19] to assess the cytokine profile of rabbit EPCs. According to this array, all cell samples analyzed in our study similarly secreted at higher levels mainly pro-angiogenic and pro-inflammatory cytokines and few anti-angiogenic, anti-inflammatory, and neuroregulatory cytokines (Table 2).…”

Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment

“…PARP inhibitors induce CCL5 secretion via the NF-B pathway in stromal fibroblasts, which in turn activate the fibroblasts in an autocrine manner [51]. Moreover, PARP inhibitors downregulate p62 by impairing PARylation of AP-1 transcription factors, resulting in cancer-associated fibroblast activation [52].…”