Abstract
Inhibitors of bromodomain and extraterminal domain (BET) proteins, a family of chromatin reader proteins, have therapeutic efficacy against various malignancies. However, the detailed mechanisms underlying the anti-tumor effects in distinct tumor types remain elusive. Here, we show a novel antitumor mechanism of BET inhibition in pancreatic ductal adenocarcinoma (PDAC). We found that JQ1, a BET inhibitor, decreased desmoplastic stroma, a hallmark of PDAC, and suppressed the growth of patient-derived tumor xenografts (PDX) of PDACs. In vivo antitumor effects of JQ1 were not always associated with the JQ1 sensitivity of respective PDAC cells, and were rather dependent on the suppression of tumor-promoting activity in cancer-associated fibroblasts (CAFs). JQ1 inhibited Hedgehog and TGF-β pathways as potent regulators of CAF activation and suppressed the expression of α-SMA, extracellular matrix, cytokines, and growth factors in human primary CAFs. Consistently, conditioned media (CM) from CAFs promoted the proliferation of PDAC cells along with the activation of ERK, AKT, and STAT3 pathways, though these effects were suppressed when CM from JQ1-treated CAFs was used. Mechanistically, chromatin immunoprecipitation experiments revealed that JQ1 reduced TGF-β–dependent gene expression by disrupting the recruitment of the transcriptional machinery containing BET proteins. Finally, combination therapy with gemcitabine plus JQ1 showed greater efficacy than gemcitabine monotherapy against PDAC in vivo. Thus, our results reveal BET proteins as the critical regulators of CAF-activation and also provide evidence that stromal remodeling by epigenetic modulators can be a novel therapeutic option for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by abundant desmoplastic stroma [1]
Using these patient-derived tumor xenografts (PDX) models, we investigated the effects of bromodomain and extraterminal domain (BET) inhibition
Several studies have reported a therapeutic efficacy of BET inhibition on pancreatic ductal adenocarcinoma (PDAC) [10,11,12], though underlying mechanisms of antitumor efficacy and how BET inhibition affects cancer-associated fibroblasts (CAFs) remain elusive
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by abundant desmoplastic stroma [1]. Cancer-associated fibroblasts (CAFs) are the most abundant cell types in the tumor stroma. CAFs are activated by soluble factors like hedgehog (Hh) ligands or TGF-β, which are secreted from PDAC cells [1]. Activated CAFs acquire tumorpromoting properties such as enhanced extracellular www.impactjournals.com/oncotarget matrix (ECM) synthesis and increased secretion of growth factors and inflammatory cytokines [2]. As CAFs have been implicated in disease progression and therapeutic resistance, CAFs have long attracted attention as a therapeutic target in PDAC. The precise mechanisms by which CAFs are activated and maintain activated phenotypes remain elusive
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