Publications by authors named "Rugang Zhang"

114 Publications

Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in -Mutant Ovarian Cancers.

Cancer Res 2021 Oct 21;81(20):5325-5335. Epub 2021 Sep 21.

Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.

The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α-XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α-XBP1 pathway in -mutant OCCC. mutational status correlated with response to inhibition of the IRE1α-XBP1 pathway. In a conditional genetic mouse model, knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of -inactivated OCCCs. These studies define the IRE1α-XBP1 axis of the ER stress response as a targetable vulnerability for -mutant OCCCs, revealing a promising therapeutic approach for treating -mutant ovarian cancers. SIGNIFICANCE: These findings indicate that pharmacological inhibition of the IRE1α-XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for -mutant ovarian cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1545DOI Listing
October 2021

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer.

Nat Commun 2021 09 7;12(1):5321. Epub 2021 Sep 7.

Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1038/s41467-021-25684-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423755PMC
September 2021

Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma.

Nat Cancer 2021 Feb 11;2(2):189-200. Epub 2021 Jan 11.

Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.

Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that mutation creates a dependence on glutamine metabolism. SWI/SNF represses () and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents an effective therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as mutations.
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http://dx.doi.org/10.1038/s43018-020-00160-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168620PMC
February 2021

The FENDRR/FOXC2 Axis Contributes to Multidrug Resistance in Gastric Cancer and Correlates With Poor Prognosis.

Front Oncol 2021 22;11:634579. Epub 2021 Mar 22.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

The dysregulation of long non-coding RNAs (lncRNAs) and transcription factors (TFs) is closely related to the development and progression of drug resistance in cancer chemotherapy. However, their regulatory interactions in the multidrug resistance (MDR) of gastric cancer (GC) has largely remained unknown. In this study, we report a novel oncogenic role of lncRNA FENDRR in conferring MDR in GC by coordinated regulation of FOXC2 expression at the transcriptional and posttranscriptional levels. and experiments demonstrated that downregulation of FENDRR expression remarkably decreased drug resistant ability of GC MDR cells while upregulation of FENDRR expression produced the opposite effect. FENDRR overexpression was observed in MDR GC cell lines, patient-derived xenografts, and clinical samples. And the high levels of FENDRR expression were correlated with poor prognosis in GC patients. Regarding the mechanism, FENDRR was revealed to increase proto-oncogene FOXC2 transcription by performing an enhancer-like role in the nucleus and by sponging miR-4700-3p in the cytoplasm. Both FOXC2 and miR-4700-3p were shown to be functionally involved in the FENDRR-induced chemoresistance. In addition, there is a positive correlation between FENDRR and FOXC2 expression in clinic and the overexpressed FOXC2 indicated a poor prognosis in GC patients. Collectively, our findings provide a new perspective for the lncRNA-TF regulatory interaction involved in MDR, suggesting that targeting the FENDRR/FOXC2 axis may be an effective approach to circumvent GC chemoresistance.
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http://dx.doi.org/10.3389/fonc.2021.634579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044876PMC
March 2021

mA-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.

Nat Cell Biol 2021 04 1;23(4):355-365. Epub 2021 Apr 1.

Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.

Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N-methyladenosine (mA) modification. Despite the expanding list of mA-dependent functions of the methyltransferase complex, the mA-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an mA-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by mA mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an mA-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.
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http://dx.doi.org/10.1038/s41556-021-00656-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035315PMC
April 2021

Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype.

iScience 2021 Jan 30;24(1):102016. Epub 2020 Dec 30.

Immunology, Metastasis and Microenvironment Program, The Wistar Institute, Philadelphia, PA 19104, USA.

Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8 T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB.
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http://dx.doi.org/10.1016/j.isci.2020.102016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811168PMC
January 2021

ARID2 Deficiency Correlates with the Response to Immune Checkpoint Blockade in Melanoma.

J Invest Dermatol 2021 Jun 15;141(6):1564-1572.e4. Epub 2020 Dec 15.

Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, Kobe, Japan.

The SWI/SNF chromatin remodeler family includes the BAF and PBAF complexes. ARID2, encoding a PBAF complex subunit, is frequently mutated in melanoma independently of BRAF/RAS mutations. Emerging evidence shows that SWI/SNF complexes regulate tumor immunity; for instance, the loss of PBRM1, another PBAF complex subunit, enhances susceptibility to immune checkpoint inhibitors in melanoma. Notably, ARID2 mutations are more frequent in melanoma than PBRM1 mutations. However, the role of ARID2 as a modulator of tumor immunity remains unclear. In this study, we show that ARID2 knockout sensitizes melanoma to immune checkpoint inhibitors. Anti‒PD-L1 treatment restricts tumor growth in mice bearing ARID2-knockout melanoma cells, correlating with an increase in the infiltration of cytotoxic CD8 T cells. Furthermore, ARID2 deficiency leads to signal transducer and activator of transcription 1 upregulation, which subsequently causes increased expression of T-cell‒attracting chemokines such as CXCL9, CXCL10, and CCL5. These results demonstrate that ARID2 is an immunomodulator and a potential biomarker that indicates immune checkpoint inhibitor effectiveness in patients with melanoma.
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http://dx.doi.org/10.1016/j.jid.2020.11.026DOI Listing
June 2021

Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils.

Sci Transl Med 2020 12;12(572)

AstraZeneca, Oncology R&D, ICC, Gaithersburg, MD 20878, USA.

Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in patients with cancer. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using dormancy models of lung and ovarian cancer, we found a specific mechanism, mediated by stress and neutrophils, that may govern this process. Stress hormones cause rapid release of proinflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase, resulting in accumulation of oxidized lipids in these cells. Upon release from neutrophils, these lipids up-regulate the fibroblast growth factor pathway in tumor cells, causing tumor cell exit from the dormancy and formation of new tumor lesions. Higher serum concentrations of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2-adrenergic receptors abrogated stress-induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress and specific neutrophil activation with early recurrence in cancer.
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http://dx.doi.org/10.1126/scitranslmed.abb5817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085740PMC
December 2020

CD38-expressing macrophages drive age-related NAD decline.

Nat Metab 2020 11;2(11):1186-1187

Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s42255-020-00292-5DOI Listing
November 2020

Targeting CARM1 in ovarian cancer with EZH2 and PARP inhibitors.

Mol Cell Oncol 2020 23;7(4):1760675. Epub 2020 May 23.

Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA, USA.

Coactivator-associated arginine methyltransferase 1 ()-expressing high-grade serous ovarian cancers are characterized by poor prognosis and limited therapeutic options. Here we discuss a novel therapeutic strategy to target CARM1-expressing ovarian cancer based on a combination of poly (ADP-ribose) polymerase (PARP) and enhancer of zeste homology 2 (EZH2) inhibitors.
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http://dx.doi.org/10.1080/23723556.2020.1760675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469455PMC
May 2020

Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models.

Nat Commun 2020 07 24;11(1):3726. Epub 2020 Jul 24.

Penn Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.
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http://dx.doi.org/10.1038/s41467-020-17127-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381609PMC
July 2020

Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors.

Cancer Immunol Immunother 2020 Sep 20;69(9):1929-1936. Epub 2020 May 20.

Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Rm. 118, 3601 Spruce Str., Philadelphia, PA, 19104, USA.

Myeloid-derived suppressor cells (MDSCs) are widely implicated in negative regulation of immune responses in cancer. Inhibition of class I histone deacetylases (HDAC) with entinostat has anti-MDSC activity. However, as single agent, it did not delay tumor growth in EL4 and LLC tumor models. Here, we found that entinostat reduced immune suppressive activity of only one type of MDSC-polymorphonuclear, PMN-MDSC, whereas it had no effect on monocytic M-MDSC or macrophages. M-MDSC had high amount of class II HDAC-HDAC6, which was further increased after the treatment of mice with entinostat. Inhibition of HDAC6 with ricolinostat reduced suppressive activity of M-MDSC, but did not affect PMN-MDSC or delayed tumor growth. However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.
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http://dx.doi.org/10.1007/s00262-020-02588-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765083PMC
September 2020

mutation and genomic stability.

Mol Cell Oncol 2020 23;7(3):1690923. Epub 2020 Feb 23.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.

We have recently discovered that AT-rich interactive domain-containing protein 1A (ARID1A) protects telomere cohesion through regulation of the cohesin subunit stromal antigen 1 (STAG1). ARID1A inactivation results in mitotic defects and negatively selects gross chromosomal aberrations, resulting in preservation of genomic stability in -mutated cancers. These findings explain the long-standing paradox between mitotic defects caused by ARID1A inactivation and the lack of genomic instability in -mutated cancers.
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http://dx.doi.org/10.1080/23723556.2019.1690923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199758PMC
February 2020

Topoisomerase 1 cleavage complex enables pattern recognition and inflammation during senescence.

Nat Commun 2020 02 19;11(1):908. Epub 2020 Feb 19.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.

Cyclic cGMP-AMP synthase (cGAS) is a pattern recognition cytosolic DNA sensor that is essential for cellular senescence. cGAS promotes inflammatory senescence-associated secretory phenotype (SASP) through recognizing cytoplasmic chromatin during senescence. cGAS-mediated inflammation is essential for the antitumor effects of immune checkpoint blockade. However, the mechanism by which cGAS recognizes cytoplasmic chromatin is unknown. Here we show that topoisomerase 1-DNA covalent cleavage complex (TOP1cc) is both necessary and sufficient for cGAS-mediated cytoplasmic chromatin recognition and SASP during senescence. TOP1cc localizes to cytoplasmic chromatin and TOP1 interacts with cGAS to enhance the binding of cGAS to DNA. Retention of TOP1cc to cytoplasmic chromatin depends on its stabilization by the chromatin architecture protein HMGB2. Functionally, the HMGB2-TOP1cc-cGAS axis determines the response of orthotopically transplanted ex vivo therapy-induced senescent cells to immune checkpoint blockade in vivo. Together, these findings establish a HMGB2-TOP1cc-cGAS axis that enables cytoplasmic chromatin recognition and response to immune checkpoint blockade.
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http://dx.doi.org/10.1038/s41467-020-14652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031389PMC
February 2020

Integrative comparison of the genomic and transcriptomic landscape between prostate cancer patients of predominantly African or European genetic ancestry.

PLoS Genet 2020 02 14;16(2):e1008641. Epub 2020 Feb 14.

Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Men of predominantly African Ancestry (AA) have higher prostate cancer (CaP) incidence and worse survival than men of predominantly European Ancestry (EA). While socioeconomic factors drive this disparity, genomic factors may also contribute to differences in the incidence and mortality rates. To compare the prevalence of prostate tumor genomic alterations and transcriptomic profiles by patient genetic ancestry, we evaluated genomic profiles from The Cancer Genome Atlas (TCGA) CaP cohort (n = 498). Patient global and local genetic ancestry were estimated by computational algorithms using genotyping data; 414 (83.1%) were EA, 61 (12.2%) were AA, 11 (2.2%) were East Asian Ancestry (EAA), 10 (2.0%) were Native American (NA), and 2 (0.4%) were other ancestry. Genetic ancestry was highly concordant with self-identified race/ethnicity. Subsequent analyses were limited to 61 AA and 414 EA cases. Significant differences were observed by ancestry in the frequency of SPOP mutations (20.3% AA vs. 10.0% EA; p = 5.6×10-03), TMPRSS2-ERG fusions (29.3% AA vs. 39.6% EA; p = 4.4×10-02), and PTEN deletions/losses (11.5% AA vs. 30.2% EA; p = 3.5×10-03). Differentially expressed genes (DEGs) between AAs and EAs showed significant enrichment for prostate eQTL target genes (p = 8.09×10-48). Enrichment of highly expressed DEGs for immune-related pathways was observed in AAs, and for PTEN/PI3K signaling in EAs. Nearly one-third of DEGs (31.3%) were long non-coding RNAs (DE-lncRNAs). The proportion of DE-lncRNAs with higher expression in AAs greatly exceeded that with lower expression in AAs (p = 1.2×10-125). Both ChIP-seq and RNA-seq data suggested a stronger regulatory role for AR signaling pathways in DE-lncRNAs vs. non-DE-lncRNAs. CaP-related oncogenic lncRNAs, such as PVT1, PCAT1 and PCAT10/CTBP1-AS, were found to be more highly expressed in AAs. We report substantial heterogeneity in the prostate tumor genome and transcriptome between EA and AA. These differences may be biological contributors to racial disparities in CaP incidence and outcomes.
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http://dx.doi.org/10.1371/journal.pgen.1008641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046294PMC
February 2020

Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy.

J Clin Invest 2020 05;130(5):2712-2726

Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BRG/BRM-associated factor chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to IFN-responsive genes, impaired IFN gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies and in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
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http://dx.doi.org/10.1172/JCI134402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190935PMC
May 2020

EZH2 Inhibition Sensitizes CARM1-High, Homologous Recombination Proficient Ovarian Cancers to PARP Inhibition.

Cancer Cell 2020 02 30;37(2):157-167.e6. Epub 2020 Jan 30.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:

In response to DNA double-strand breaks, MAD2L2-containing shieldin complex plays a critical role in the choice between homologous recombination (HR) and non-homologous end-joining (NHEJ)-mediated repair. Here we show that EZH2 inhibition upregulates MAD2L2 and sensitizes HR-proficient epithelial ovarian cancer (EOC) to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor in a CARM1-dependent manner. CARM1 promotes MAD2L2 silencing by driving the switch from the SWI/SNF complex to EZH2 through methylating the BAF155 subunit of the SWI/SNF complex on the MAD2L2 promoter. EZH2 inhibition upregulates MAD2L2 to decrease DNA end resection, which increases NHEJ and chromosomal abnormalities, ultimately causing mitotic catastrophe in PARP inhibitor treated HR-proficient cells. Significantly, EZH2 inhibitor sensitizes CARM1-high, but not CARM-low, EOCs to PARP inhibitors in both orthotopic and patient-derived xenografts.
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http://dx.doi.org/10.1016/j.ccell.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155421PMC
February 2020

Breast Cancer Image Classification via Multi-level Dual-network Features and Sparse Multi-Relation Regularized Learning.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:7023-7026

Breast cancer is one of the leading causes of cancer death worldwide. Recently, the computer-aided diagnosis and detection technique has been developed for the early diagnosis of breast cancer, but the diagnostic efficiency has still been a challenging issue. For this reason, we aim to improve the breast cancer diagnostic accuracy and reduce the workload of doctors in this paper by devising a deep learning framework based on histological image. Therefore, we develop a model of multi-level feature of dual-network combined with sparse multi-relation regularized learning method, which enhances the classification performance and robustness. Specifically, first, we preprocess the histological images using scale transformation and color enhancement methods. Second, the multi-level features are extracted from preprocessed images using InceptionV3-ML and ResNet-50 networks. Third, the feature selection method via sparse multi-relation regularization is further developed for performance boosting and overfitting reduction. We evaluate the proposed method based on the public ICIAR 2018 Challenge dataset of breast cancer histology images. Experimental results show that our method has achieved promising performance and outperformed the related works.
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http://dx.doi.org/10.1109/EMBC.2019.8857762DOI Listing
July 2019

NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer.

Cancer Res 2020 02 19;80(4):890-900. Epub 2019 Dec 19.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both and . Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024650PMC
February 2020

Involvement of condensin in cellular senescence through gene regulation and compartmental reorganization.

Nat Commun 2019 12 12;10(1):5688. Epub 2019 Dec 12.

Institute of Molecular Biology, University of Oregon, Eugene, OR, 97403, USA.

Senescence is induced by various stimuli such as oncogene expression and telomere shortening, referred to as oncogene-induced senescence (OIS) and replicative senescence (RS), respectively, and accompanied by global transcriptional alterations and 3D genome reorganization. Here, we demonstrate that the human condensin II complex participates in senescence via gene regulation and reorganization of euchromatic A and heterochromatic B compartments. Both OIS and RS are accompanied by A-to-B and B-to-A compartmental transitions, the latter of which occur more frequently and are undergone by 14% (430 Mb) of the human genome. Mechanistically, condensin is enriched in A compartments and implicated in B-to-A transitions. The full activation of senescence genes (SASP genes and p53 targets) requires condensin; its depletion impairs senescence markers. This study describes that condensin reinforces euchromatic A compartments and promotes B-to-A transitions, both of which are coupled to optimal expression of senescence genes, thereby allowing condensin to contribute to senescent processes.
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http://dx.doi.org/10.1038/s41467-019-13604-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908677PMC
December 2019

Observation of immediate and mid-term effects of partial spleen embolization in reducing hepatic venous pressure gradient.

Medicine (Baltimore) 2019 Nov;98(47):e17900

Department of Gastroenterology, Hainan Hospital of PLA General Hospital, Haitang District, Sanya, Hainan.

Objective: To observe the immediate and mid-term effects of partial spleen embolization (PSE) in reducing hepatic venous pressure gradient (HVPG) in patients with cirrhotic esophagogastric varices.

Methods: Patients diagnosed with cirrhosis and esophagogastric varices in our hospital between July 2016 and March 2018 were consecutively selected. Forty-three patients were selected based on the eligibility criteria to undergo PSE. The change in HVPG 5 minutes before and after embolization, was used to determine the immediate effect of PSE on HVPG reduction. HVPG was retested after 6 months to observe the change in the antihypertensive effect along with time.

Results: Forty-three patients successfully underwent PSE and HVPG measurements. The HVPG was 17.7 ± 3.9 mmHg and 13.9 ± 3.1 mmHg before and after PSE, respectively, showing a significant decrease (21.5%, P < .05). Among them, 18 cases were retested for HVPG at 6 months after PSE, and the results showed significant differences in the HVPG levels before, immediately and 6 months after PSE. Compared with preoperative PSE, HVPG was decreased by 22.9% and 17.7% (P < 0.05) immediately and at 6 months after operation, respectively. There was no significant change at 6 months after PSE when compared with immediate postoperative PSE. No serious complications were observed in patients during their postoperative hospital stay.

Conclusion: PSE immediately reduced the portal pressure, and HVPG remained stable at 6 months after surgery. PSE is considered as a safe and easy to implement method, and is expected to be one of the treatments for reducing the portal pressure.
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http://dx.doi.org/10.1097/MD.0000000000017900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882594PMC
November 2019

ARID1A promotes genomic stability through protecting telomere cohesion.

Nat Commun 2019 09 6;10(1):4067. Epub 2019 Sep 6.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.

ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G/M, but not G phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A-mutated cancers.
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http://dx.doi.org/10.1038/s41467-019-12037-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731242PMC
September 2019

HDAC6 Inhibition Synergizes with Anti-PD-L1 Therapy in ARID1A-Inactivated Ovarian Cancer.

Cancer Res 2019 11 16;79(21):5482-5489. Epub 2019 Jul 16.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.

encoding a subunit of the SWI/SNF complex, is the most frequently mutated epigenetic regulator in human cancers and is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), a disease that currently has no effective therapy. Inhibition of histone deacetylase 6 (HDAC6) suppresses the growth of -mutated tumors and modulates tumor immune microenvironment. Here, we show that inhibition of HDAC6 synergizes with anti-PD-L1 immune checkpoint blockade in ARID1A-inactivated ovarian cancer. ARID1A directly repressed transcription of , the gene encoding PD-L1. Reduced tumor burden and improved survival were observed in OCCC mice treated with the HDAC6 inhibitor ACY1215 and anti-PD-L1 immune checkpoint blockade as a result of activation and increased presence of IFNγ-positive CD8 T cells. We confirmed that the combined treatment limited tumor progression in a cytotoxic T-cell-dependent manner, as depletion of CD8 T cells abrogated these antitumor effects. Together, these findings indicate that combined HDAC6 inhibition and immune checkpoint blockade represents a potential treatment strategy for -mutated cancers. SIGNIFICANCE: These findings offer a mechanistic rationale for combining epigenetic modulators and existing immunotherapeutic interventions against a disease that has been so far resistant to checkpoint blockade as a monotherapy..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825538PMC
November 2019

NAD metabolism controls inflammation during senescence.

Mol Cell Oncol 2019 29;6(4):1605819. Epub 2019 Apr 29.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.

We have recently discovered that nicotinamide adenine dinucleotide metabolism controls the pro-inflammatory senescence-associated secretory phenotype during cellular senescence. This newly discovered epigenetic-metabolic signaling axis, mediated by high mobility group A and nicotinamide phosphoribosyltransferase, drives key metabolic changes and pro-inflammatory responses of senescent cells that fuel cancer progression.
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http://dx.doi.org/10.1080/23723556.2019.1605819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548475PMC
April 2019

ARID1A spatially partitions interphase chromosomes.

Sci Adv 2019 05 22;5(5):eaaw5294. Epub 2019 May 22.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.

ARID1A, a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex, localizes to both promoters and enhancers to influence transcription. However, the role of ARID1A in higher-order spatial chromosome partitioning and genome organization is unknown. Here, we show that ARID1A spatially partitions interphase chromosomes and regulates higher-order genome organization. The SWI/SNF complex interacts with condensin II, and they display significant colocalizations at enhancers. ARID1A knockout drives the redistribution of condensin II preferentially at enhancers, which positively correlates with changes in transcription. ARID1A and condensin II contribute to transcriptionally inactive B-compartment formation, while ARID1A weakens the border strength of topologically associated domains. Condensin II redistribution induced by ARID1A knockout positively correlates with chromosome sizes, which negatively correlates with interchromosomal interactions. ARID1A loss increases the trans interactions of small chromosomes, which was validated by three-dimensional interphase chromosome painting. These results demonstrate that ARID1A is important for large-scale genome folding and spatially partitions interphase chromosomes.
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http://dx.doi.org/10.1126/sciadv.aaw5294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531001PMC
May 2019

N-Methylation of Adenosine of mRNA Contributes to PARP Inhibitor Resistance.

Cancer Res 2019 06 9;79(11):2812-2820. Epub 2019 Apr 9.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania.

Despite the high initial response rates to PARP inhibitors (PARPi) in -mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N-methyladenosine (mA) is the most abundant chemical modification of mRNA, yet the role of mA modification in PARPi resistance has not previously been explored. Here, we show that mA modification of mRNA contributes to PARPi resistance by upregulating the Wnt/β-catenin pathway in -mutated EOC cells. Global mA profile revealed a significant increase in mA modification in mRNA, which correlated with increased mRNA stability and an upregulation of the Wnt/β-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/β-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of mA demethylases FTO and ALKBH5 was sufficient to increase mRNA mA modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/β-catenin showed synergistic suppression of PARPi-resistant cells and in a xenograft EOC mouse model. Overall, our results show that mA contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/β-catenin pathway via stabilization of . They also suggest that inhibition of the Wnt/β-catenin pathway represents a potential strategy to overcome PARPi resistance. SIGNIFICANCE: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that mA modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/β-catenin pathway.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548690PMC
June 2019

Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference.

Cancer 2019 06 5;125(12):1963-1972. Epub 2019 Mar 5.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.
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http://dx.doi.org/10.1002/cncr.32004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557260PMC
June 2019

NAD metabolism governs the proinflammatory senescence-associated secretome.

Nat Cell Biol 2019 03 18;21(3):397-407. Epub 2019 Feb 18.

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.

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.
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http://dx.doi.org/10.1038/s41556-019-0287-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448588PMC
March 2019

Epigenetic inhibitors for the precision treatment of -mutant ovarian cancers: what are the next steps?

Expert Rev Precis Med Drug Dev 2018 25;3(4):233-236. Epub 2018 Jul 25.

Department of Obstetrics & Gynecology, University of Colorado Anschutz Medical Campus, Research Complex-2; MS8613, 12700 East 19th Avenue, Aurora, Colorado 80045.

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http://dx.doi.org/10.1080/23808993.2018.1503050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277026PMC
July 2018

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers.

Cancer Cell 2018 10;34(4):549-560.e9

Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities.
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http://dx.doi.org/10.1016/j.ccell.2018.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348897PMC
October 2018
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