Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses ...PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.
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•BET inhibitors suppress PD-L1 expression in both immune cells and tumor cells•CD274 is a direct target gene of BRD4•BET inhibitors increase cytotoxic T cell activity to limit tumor progression in mice
Zhu et al. find that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer in mice. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. Together, these data suggest a small-molecule approach to blocking PD-L1 signaling.
Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to ...the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E
. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.
Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the ...senescence-associated secretory phenotype (SASP). NAD
metabolism influences both tissue ageing and cancer. However, the role of NAD
metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD
salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD
signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD
-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD
metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD
augmentation should be administered with precision.
Experiments of nature have revealed the peculiar importance of the G-protein-coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest ...in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and "stemness". Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab), are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which ...currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
Mitochondria must buffer the risk of proteotoxic stress to preserve bioenergetics, but the role of these mechanisms in disease is poorly understood. Using a proteomics screen, we now show that the ...mitochondrial unfoldase-peptidase complex ClpXP associates with the oncoprotein survivin and the respiratory chain Complex II subunit succinate dehydrogenase B (SDHB) in mitochondria of tumor cells. Knockdown of ClpXP subunits ClpP or ClpX induces the accumulation of misfolded SDHB, impairing oxidative phosphorylation and ATP production while activating "stress" signals of 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy. Deregulated mitochondrial respiration induced by ClpXP targeting causes oxidative stress, which in turn reduces tumor cell proliferation, suppresses cell motility, and abolishes metastatic dissemination in vivo. ClpP is universally overexpressed in primary and metastatic human cancer, correlating with shortened patient survival. Therefore, tumors exploit ClpXP-directed proteostasis to maintain mitochondrial bioenergetics, buffer oxidative stress, and enable metastatic competence. This pathway may provide a "drugable" therapeutic target in cancer.
In addition to adenosine-to-inosine RNA editing activities, ADAR1 has been shown to have various RNA editing-independent activities including modulation of RNAi efficacy. We previously reported that ...ADAR1 forms a heterodimer complex with DICER and facilitates processing of pre-miRNAs to mature miRNAs. In addition to miRNA synthesis, DICER is involved in processing of long dsRNAs into small RNAs (endo-siRNAs). Generation of retrotransposon-derived endo-siRNAs by DICER and their functions in regulation of transcripts in mouse oocytes has been previously reported. However, the synthesis and functions of endo-siRNAs in somatic cells remain largely unknown. Here, we report that ADAR1 together with DICER generates endogenous small RNAs,
endo-siRNAs by cleaving long double-stranded regions of inverted
repeats. We identified AGO2-loaded
endo-siRNAs, which are highly expressed in commonly used cell lines. These
endo-siRNAs carrying both sense and antisense
sequences seem to target a set of genes containing a single
sequence, either antisense or sense, respectively, within their 3'UTR. In silico screening identified potential RNA silencing target genes for these
endo-siRNAs. We present results of a proof-of-concept experiment, in which sense
endo-siRNAs derived from
and
family elements target CUB Domain Containing Protein 1 mRNAs containing an antisense copy of
in their 3'UTRs and consequently induce apoptosis in HeLa cells. Our results clearly indicate that
endo-siRNAs are functional also in somatic cells.
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain ...inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe. Moreover, JQ1 and Olaparib showed synergistic suppression of growth of BRCA-proficient cancer in vivo in a xenograft ovarian cancer mouse model. Our findings indicate that a combination of BET inhibitor and PARP inhibitor represents a potential therapeutic strategy for BRCA-proficient cancers.
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•BET inhibitor suppresses TOPBP1 and WEE1 expression•BET inhibitor and PARP inhibitor induce apoptosis in a synergistic manner•Combined BET and PARP inhibition causes mitotic catastrophe•BET and PARP inhibition synergize in suppressing BRCA1/2 wild-type ovarian tumors
Karakashev et al. show synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers. This combination of inhibitors can synergistically increase DNA damage and cell-cycle checkpoint defects, which allows cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe.
CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive ...responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.
The crosstalk between tumor cells and the adjacent normal epithelium contributes to cancer progression, but its regulators have remained elusive. Here, we show that breast cancer cells maintained in ...hypoxia release small extracellular vesicles (sEVs) that activate mitochondrial dynamics, stimulate mitochondrial movements, and promote organelle accumulation at the cortical cytoskeleton in normal mammary epithelial cells. This results in AKT serine/threonine kinase (Akt) activation, membrane focal adhesion turnover, and increased epithelial cell migration. RNA sequencing profiling identified integrin-linked kinase (ILK) as the most upregulated pathway in sEV-treated epithelial cells, and genetic or pharmacologic targeting of ILK reversed mitochondrial reprogramming and suppressed sEV-induced cell movements. In a three-dimensional (3D) model of mammary gland morphogenesis, sEV treatment induced hallmarks of malignant transformation, with deregulated cell death and/or cell proliferation, loss of apical-basal polarity, and appearance of epithelial-to-mesenchymal transition (EMT) markers. Therefore, sEVs released by hypoxic breast cancer cells reprogram mitochondrial dynamics and induce oncogenic changes in a normal mammary epithelium.
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•Hypoxic breast cancer cells release signaling sEVs•sEVs activate mitochondrial dynamics in recipient normal mammary epithelium•Mitochondrial reprogramming stimulates ILK-Akt-dependent epithelial cell migration•sEVs disrupt normal mammary gland morphogenesis with hallmarks of malignancy
The communication between tumor cells and their neighbors is important for disease progression. Here, Bertolini et al. show that hypoxic breast cancer cells release small extracellular vesicles that introduce multiple malignant changes in the normal mammary epithelium via reprogramming of mitochondrial functions. This pathway may promote local breast cancer recurrences.
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