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  • American Association for Cancer Research (AACR)  (23)
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  • American Association for Cancer Research (AACR)  (23)
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  • 1
    Online Resource
    Online Resource
    Abstract A09: Diet-induced obesity promotes breast cancer progression by LPA-signaling-mediated functional changes of mitochondria and angiogenesis
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 1_Supplement ( 2015-01-01), p. A09-A09
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 1_Supplement ( 2015-01-01), p. A09-A09
    Abstract: Despite insight that obesity greatly increases cancer risk including breast cancer (BC) is supported by epidemiological studies, the direct link and mechanisms by which obesity increases BC risk remain largely unknown. Nutritional obesity is associated with a prediabetic state characterized by alteration in glucose homeostasis. The increased glucose level may aid cancer cells in generating metabolic advantage. Obesity is also accompanied by an autotaxin (ATX) mediated synthesis of bioactive signaling phospholipid or lysophosphatidic acid (LPA). ATX and plasma LPA are up-regulated in diet-induced obese (DIO) mice. We have shown that LPA stimulated angiogenesis via turning off CD36 antiangiogenic switch in endothelial cells (ECs) via protein kinase PKD-1 pathway. We hypothesize that obesity-derived LPA is a key bona fide tumor promoter by modifying mitochondrial bioenergetic metabolism and stimulating BC angiogenesis in response to high glucose. Using Seahorse Bioscience Extracellular Flux Analyzer, we discovered that LPA enhanced mitochondrial respiration of human breast adenocarcinoma cell MDA-MB231 transduced with wild type PKD-1 (PKD-WT) under high glucose conditions. LPA exposure significantly changed oxygen consumption rate (OCR), ATP linked OCAR but not extracellular acidification rate (ECAR) in cells exposed to high glucose. However, the change of OCR was attenuated by a selective PKD inhibitor CID755673. Furthermore, when exposed to conditional medium from human microvascular endothelial cells (HMVECs), MDA-MB231 overexpressing PKD-WT showed lower levels of basal OCR, ATP linked OCAR and ECAR compared with control medium. Obesity-derived LPA also inhibited CD36 expression in tumor-associated ECs and promoted BC cell growth, which was partially abolished by ATX inhibitor. Intriguingly, CID755673 inhibited clonogenic survival of MDA-MB231. To determine in vivo mechanisms of obesity-derived LPA, we established a syngeneic BC model by subcutaneously implanting E0771 adenocarcinoma in female C57BL/6J mice. DIO greatly promoted BC development in mice, demonstrated by huge tumors in DIO but not in control mice. DIO mice also showed increase in LPA receptor 1 in tumor endothelium, with robust angiogenesis and extensive bleeding inside tumor. Additionally, a high level of PD-1 expression was found in CD8 T cells inside the tumor in obese mice, implicating diet-induced obesity leads to T cell dysfunction. Our data suggests that LPA is a key player in BC angiogenesis and development but it is not the only mediator responsible for obesity-induced tumor progression. LPA-stimulated tumor progression may be associated with alternation of bioenergetic function via PKD signaling under high glucose conditions. DIO-enhanced LPA signaling may contribute to EC CD36 downregulation and dysregulated mitochondrial functions, leading to proangiogenic responses in tumor microenvironment. DIO-stimulated LPA signaling could modulate switch between mitochondrial oxidative phosphorylation and aerobic glycolysis in both BC and tumor endothelium. Targeting LPA-PKD-metabolic signaling axis may provide a novel therapeutic strategy. Citation Format: Ye Yuan, Jacob D. Kohlenberg, Yiliang Chen, Steve Komas, Gang Xin, Gloria Yuan, Weiguo Cui, Shiyong Wu, Bin Ren. Diet-induced obesity promotes breast cancer progression by LPA-signaling-mediated functional changes of mitochondria and angiogenesis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A09. doi:10.1158/1538-7445.CHTME14-A09
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.CHTME14-A09
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Targeting PIM1-Mediated Metabolism in Myeloid Suppressor Cells to Treat Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Immunology Research Vol. 9, No. 4 ( 2021-04-01), p. 454-469
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 4 ( 2021-04-01), p. 454-469
    Abstract: There is a strong correlation between myeloid-derived suppressor cells (MDSC) and resistance to immune checkpoint blockade (ICB), but the detailed mechanisms underlying this correlation are largely unknown. Using single-cell RNA sequencing analysis in a bilateral tumor model, we found that immunosuppressive myeloid cells with characteristics of fatty acid oxidative metabolism dominate the immune-cell landscape in ICB-resistant subjects. In addition, we uncovered a previously underappreciated role of a serine/threonine kinase, PIM1, in regulating lipid oxidative metabolism via PPARγ-mediated activities. Enforced PPARγ expression sufficiently rescued metabolic and functional defects of Pim1−/− MDSCs. Consistent with this, pharmacologic inhibition of PIM kinase by AZD1208 treatment significantly disrupted the myeloid cell–mediated immunosuppressive microenvironment and unleashed CD8+ T-cell–mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized nonresponders to PD-L1 blockade by selectively targeting suppressive myeloid cells. Overall, we have identified PIM1 as a metabolic modulator in MDSCs that is associated with ICB resistance and can be therapeutically targeted to overcome ICB resistance.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-20-0433
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2732517-9
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  • 3
    Online Resource
    Online Resource
    Abstract B201: Exploration and exploitation of macrophage death pathways: Infection by Mycobacterium tuberculosis as a model
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. B201-B201
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. B201-B201
    Abstract: Macrophages can impact the development of tumors and their responses to therapy. However, we lack a full understanding of how macrophage activation and survival are regulated and might be therapeutically modulated. To address these questions, we turned to a host-pathogen interaction that is likely to have impacted the evolution of these processes: infection by Mycobacterium tuberculosis (Mtb), the leading cause of death from infection. Once internalized by macrophages, Mtb resists killing by macrophages and replicates within them. Ultimately, Mtb infection results in death of macrophages, allowing dissemination of the pathogen to other cells. To explore how Mtb induces macrophage cell death and how macrophage cell death might impact host defense against Mtb, we performed a genome-wide CRISPR-Cas9 recessive genetic screen in RAW264.7 macrophages. We discovered that the absence of components of the type I interferon signaling pathway, including the IFN-α/β receptor (IFNAR), delays Mtb-induced cell death. It is known that Mtb infection induces macrophages to produce type I interferon. Our finding directly links type I interferon signaling pathway and Mtb-induced macrophage death. We are currently working on the mechanism of the type I IFN-induced death of bacterially-stimulated macrophages. Meanwhile, we are testing blockers of this pathway as host-directed therapy against TB and have seen striking protective effects of anti-IFNAR1 mAb in Mtb-infected mice, whether the mAb is administered before or after infection. Further exploration of the protective effect of anti-IFNAR mAb could point to an antibody-based, host-directed therapy. Acknowledgment: We thank Prof. R. Schreiber, Washington University, for facilitating access to anti-IFNAR mAb. Citation Format: Ryan Zander, David Schauder, Gang Xin, Christine Nguyen, Xiaopeng Wu, Weiguo Cui. Exploration and exploitation of macrophage death pathways: Infection by Mycobacterium tuberculosis as a model [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B201.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-B201
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
    Online Resource
    Online Resource
    Abstract B200: Single-cell RNA-sequencing (ScRNA-seq) reveals broad heterogeneity among CD8 T-cells during chronic viral infection and identifies a critical role for CD4 help in promoting the differentiation of a potent cytotoxic CD8 T-cell subset
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. B200-B200
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. B200-B200
    Abstract: During chronic viral infection and cancer, CD8 T-cells undergo a differentiation process commonly referred to as T-cell exhaustion. This process is traditionally defined by a stepwise loss of effector functions, eventually leading to cell death. Despite their inability to completely clear the infection, exhausted T-cells are still necessary for limiting viral replication during infection. Thus, it has been proposed that functional adaptation is a more appropriate term for T-cell exhaustion, as CD8 T-cells may be undergoing a multifaceted process of differentiation to better meet the needs of a chronic infection. In line with this hypothesis, it has recently been demonstrated that CD8 T-cells responding to chronic infection are non-homogenous and can be compartmentalized into at least two major subsets, with a TCF-1+ subset serving as a progenitor population that can give rise to a more terminally exhausted TCF-1- subset. However, whether additional heterogeneity exists among CD8 T-cells responding to persistent infection remains unclear. Here, we used ScRNA-seq to fully characterize the heterogeneity of CD8 T-cells during chronic LCMV Cl13 infection. We identified that several transcriptionally distinct subsets of CD8 T-cells develop during chronic LCMV infection, with 3 particular clusters, Slamf6, Pdcd1, and Cx3cr1 cell subsets dominating the antiviral CD8 T-cell response. Importantly both ScRNA-seq and flow cytometric analyses demonstrated that differential expression of cell surface receptors CX3CR1 and Ly108 (encoded by Slamf6) can distinguish these 3 major T-cell subsets. Notably, Ly108 cells shared similar characteristics to the previously described progenitor population and displayed elevated expression of TCF-1. Conversely, CX3CR1 CD8 T-cells displayed increased expression of killer cell lectin-like receptors Klre1 and Klra9, and the TFs T-bet and Zeb2, whereas CX3CR1-Ly108- (DN) cells exhibited elevated expression of multiple co-inhibitory receptors and the TFs Eomes and Nr4a2. Ex vivo functional analyses further indicated that Ly108 CD8 T-cells exhibit an enhanced capacity to co-produce IFN-γ and TNF-α upon GP33 peptide stimulation, whereas CX3CR1 CD8 T-cells display augmented cytotoxicity against peptide-pulsed targeT-cells. Sc trajectory modeling using Monocle analyses predicted that Ly108 CD8 T-cells give rise to both CX3CR1 and DN subsets, with the DN subset branch appearing closer in pseudotime to the Ly108 progenitor subset. To determine the in vivo differentiation trajectory, proliferative potential, and phenotypic stability of these 3 subsets, we performed adoptive transfer experiments using congenically marked CD8 T-cells. Importantly, and consistent with our Monocle predictions, our results demonstrate that Ly108 CD8 T-cells display robust secondary proliferation and give rise to both CX3CR1 and DN subsets. By contrast, CX3CR1 cells retained high CX3CR1 and T-bet expression and did not differentiate into Ly108 or DN CD8 T-cells. Intriguingly, although the DN subset appeared to be the most phenotypically and functionally exhausted subset, more than half of their progeny acquired high CX3CR1 and T-bet expression, indicating that this subset may not be as terminally differentiated as its CX3CR1 counterpart. Notably, our ScRNA-seq analyses also identified that DN cells displayed the highest levels of IL-21R expression, suggesting a potential role for CD4 help in regulating the differentiation of this subset. Strikingly, depletion of CD4 T-cells or deletion of IL-21R signaling in P14 transgenic CD8 T-cells abrogated the development of the CX3CR1 CD8 subset, indicating a critical role for CD4 help in facilitating the differentiation of exhausted CD8 T-cells into a potent cytotoxic CD8 subset. Collectively, our work supports a new model of CD8 T-cell differentiation during chronic viral infection and has important implications for T-cell-based immunotherapies aimed at treating persistent infections and/or cancer. Citation Format: Ryan Zander, David Schauder, Gang Xin, Christine Nguyen, Xiaopeng Wu, Weiguo Cui. Single-cell RNA-sequencing (ScRNA-seq) reveals broad heterogeneity among CD8 T-cells during chronic viral infection and identifies a critical role for CD4 help in promoting the differentiation of a potent cytotoxic CD8 T-cell subset [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B200.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-B200
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
    Online Resource
    Online Resource
    CSTF2-Induced Shortening of the RAC1 3′UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 20 ( 2018-10-15), p. 5848-5862
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 20 ( 2018-10-15), p. 5848-5862
    Abstract: Shortening of the 3′ untranslated regions (3′UTR) of mRNA is an important mechanism for oncogene activation. However, 3′UTR alteration events, their pathologic functions, and underlying mechanisms in human urothelial carcinoma of the bladder (UCB) are not clear. Here, we combine RNA sequencing, bioinformatics, and clinical studies in two independent cohorts of patients with UCB to identify a novel RAC1 shorter 3′UTR isoform that is frequently expressed in UCB and is critical in the tumorigenesis and acquisition of a poor prognostic phenotype in patients. Short 3′UTR isoform of RAC1 substantially upregulated RAC1 expression by escaping from miRNA-targeted repression and played an essential oncogenic role in UCB pathogenesis. An important cleavage/polyadenylation factor, cleavage stimulation factor 2 (CSTF2), induced 3′UTR shortening of RAC1 in UCB by mediating slow transcriptional elongation at RAC1. Cotranscriptional recruitment of CSTF2 on the GUAAU motif at proximal polyadenylation site of RAC1 attenuated the recruitment of two transcription factors AFF1 and AFF4, causing the defects in elongation. CSTF2 regulated the tumorigenic functions of the shorter RAC1 isoform in UCB cells, enhancing cell proliferation, migration, and invasion. The combination of high expression of CSTF2 and high usage of RAC1 short-3′UTR isoform may be used as a powerful biomarker to predict poor prognosis in UCB. Our findings also suggest a CSTF2-regulated RAC1-3′UTR shortening program as an exploitable therapeutic strategy for patients with UCB. Significance: These findings demonstrate that the short isoform of RAC1 is critical in UCB tumorigenesis and may have implications for developing new therapeutic strategies to treat this disease. Cancer Res; 78(20); 5848–62. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-0822
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract 38: Large-scale study of NTRK fusions in Chinese solid tumors and using next generation sequencing: A multicenter study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 38-38
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 38-38
    Abstract: Background: NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 are oncogenic drivers of various solid tumor types but generally at a low frequency. TRK inhibitors such as LOXO-101, entrectinib, X396, AB-106, TL118 had remarkable and durable antitumor activities in patients (pts) with TRK fusion-positive cancers, regardless of age or tumor type. We assessed the frequency of NTRK fusions across 14, 491 advanced cancers to reveal the landscape in a wide variety of subtypes. Methods: A multicenter study in China was initiated from July 2013, and advanced cancer patients have been enrolled as of September 2018. We analyzed data from 14, 491 clinical advanced cancer cases, each of which had results from next-generation sequencing (NGS)-based 381 genes panel assay, analogous to the index patient. Results: Of this entire cohort [6837 lung cancer (47.18%), 1894 breast cancer (13.07%), 1325 colorectal cancer (9.14%), 312 soft tissue sarcoma (2.15%), 260 head and neck cancer (1.79%) and 1804 others (12.45%)], 40 patients were identified with NTRK fusions, including TPM3-NTRK1, LMNA-NTRK1, IRF2BP2-NTRK1, TPR-NTRK1, SQSTM1-NTRK1, C1orf111-NTRK1, NTRK1-CUL3, LIPI-NTRK1, NTRK1-C1orf61, TARDBP-NTRK1, LOC643387-NTRK1, NFASC-NTRK1, RFWD2-NTRK1, MSN-NTRK2, ATL2-NTRK2, AGTPBP1-NTRK2, ZCCHC7-NTRK2, CALR-NTRK2, ESRP1-NTRK2, ETV6-NTRK3. NTRK fusions were seen in 0.26% (18/6837) of lung cancer [C1orf111-NTRK1+TPM3-NTRK1(1), TPR-NTRK1(1), TPM3-NTRK1(2), SQSTM1-NTRK1+NTRK1-CUL3(1), LIPI-NTRK1(1), NTRK1-C1orf61(1), LMNA-NTRK1(1), MSN-NTRK2(1), TARDBP-NTRK1+LOC643387-NTRK1(1), IRF2BP2-NTRK1(1), ATL2-NTRK2 (1), NFASC-NTRK1(1), AGTPBP1-NTRK2(1), RFWD2-NTRK1(1), ZCCHC7-NTRK2(1), CALR-NTRK2(1) and ESRP1-NTRK2] ; 0.21%(4/1894) of breast cancer [ETV6-NTRK3(4)]; 0.37%(5/1325) of colorectal cancer [TPM3-NTRK1(1), ETV6-NTRK3(4)] ; 3.53%(11/312) of soft tissue sarcoma [LMNA-NTRK1(3), TPM3-NTRK1(1), ETV6-NTRK3(7)]; 0.38%(1/260) of head and neck cancer [ETV6-NTRK3(1)] and 0.05%(1/1804) of others [ETV6-NTRK3(1)]. Conclusion: NTRK fusions are a rare molecular subtype in Chinese solid tumors. The NTRK gene fusions more commonly occurred in NSCLC (0.3%), CRC (0.4%) and BC (0.2%), and may occur without other targetable alterations such as EGFR, ALK, ROS1. The clinical evidence for responsiveness of NTRK fusions driven solid tumors provides an opportunity to personalize treatments and improve clinical outcomes for patients (pts). Citation Format: Wen-xian Wang, Chun-wei Xu, Lei Lei, Xiao-jia Wang, You-cai Zhu, Yong Fang, Xiu-yu Cai, Rong-bo Lin, Li Lin, Hong Wang, Mei-yu Fang, Yin-bin Zhang, Shi-jie Lan, Xin Cai, Xin Liu, Xing-xiang Pu, Zong-yang Yu, Bing Wan, Jin-luan Li, Xian-bin Liang, Li-ping Wang, Wu Zhuang, Zi-yan Yang, Gang Chen, Tang-feng Lv, Yong Song. Large-scale study of NTRK fusions in Chinese solid tumors and using next generation sequencing: A multicenter study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 38.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-38
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 7
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    Circulating Tumor Cells with Stem-Like Phenotypes for Diagnosis, Prognosis, and Therapeutic Response Evaluation in Hepatocellular Carcinoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 9 ( 2018-05-01), p. 2203-2213
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 9 ( 2018-05-01), p. 2203-2213
    Abstract: Background: In the present study, we assessed the clinical value of circulating tumor cells (CTC) with stem-like phenotypes for diagnosis, prognosis, and surveillance in hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC) by an optimized qPCR-based detection platform. Methods: Differing subsets of CTCs were investigated, and a multimarker diagnostic CTC panel was constructed in a multicenter patient study with independent validation (total n = 1,006), including healthy individuals and patients with chronic hepatitis B infection (CHB), liver cirrhosis (LC), benign hepatic lesion (BHL), and HBV-related HCC, with area under the receiver operating characteristic curve (AUC-ROC) reflecting diagnostic accuracy. The role of the CTC panel in treatment response surveillance and its prognostic significance were further investigated. Results: The AUC of the CTC panel was 0.88 in the training set [sensitivity = 72.5%, specificity = 95.0%, positive predictive value (PPV) = 92.4, negative predictive value (NPV) = 77.8] and 0.93 in the validation set (sensitivity = 82.1%, specificity = 94.2%, PPV = 89.9, NPV = 89.3). This panel performed equally well in detecting early-stage and α-fetoprotein–negative HCC, as well as differentiating HCC from CHB, LC, and BHL. The CTC load was decreased significantly after tumor resection, and patients with persistently high CTC load showed a propensity of tumor recurrence after surgery. The prognostic significance of the CTC panel in predicting tumor recurrence was further confirmed [training: HR = 2.692; 95% confidence interval (CI), 1.617–4.483; P & lt; 0.001; and validation: HR = 3.127; 95% CI, 1.360–7.190; P = 0.007]. Conclusions: Our CTC panel showed high sensitivity and specificity in HCC diagnosis and could be a real-time parameter for risk prediction and treatment monitoring, enabling early decision-making to tailor effective antitumor strategies. Clin Cancer Res; 24(9); 2203–13. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-1753
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Abstract 3671: Visualize 10,000 whole-genomes from pediatric cancer patients on St. Jude Cloud
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3671-3671
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3671-3671
    Abstract: Whole-genome sequencing (WGS) is invaluable for investigating genetic abnormalities contributing to the initiation, progression and long-term clinical outcome of pediatric cancer. St. Jude Cloud (https://www.stjude.cloud/) hosts 10,000 (10K) harmonized WGS samples generated from: 1) St. Jude/Washington University Pediatric Cancer Genome Project, 2) the Genomes for Kids Clinical Trial, 3) the St. Jude Lifetime Cohort Study, and 4) the Childhood Cancer Survivor Study. To enable on-the-cloud discovery and eliminate the need for data download, we developed GenomePaint, an interactive genomics browser, to explore the somatic and germline variants of the 10K genomes with rich annotation. Germline variants in cancer predisposition genes were annotated for pathogenicity. Using GenomePaint, users can compare pathogenic variants from a locus of interest across multiple cancers or test for association of a germline variant with a specific cancer type on the fly. By matching germline variants to somatic mutation hotspots from www.cancerhotspots.org, we annotated potential germline mosaic mutations including IDH1 R132H, FBXW7 R465C, and KRAS A146T. For noncoding variants, we investigated overlap with ATAC and DNase peaks in 50 cancer cell lines along with transcription factor motif change predictions. These features will enable exploration of the functional impact of genetic variations with potential clinical status such as genetic risk for a specific cancer type, genetic association with age of onset, or development of subsequent malignancies for pediatric cancer survivors. GenomePaint also provides an integrated view of somatic SNV/indel, copy number variation, loss-of-heterozygosity, structural variation, and gene fusion. These are shown together with tumor gene expression at the single tumor level. GenomePaint also presents allele-specific expression (ASE) and outlier expression as an indicator for assessing dysfunction of regulatory regions caused by genomic variants. Cloud-based on-the-fly ASE analysis is also available for user’s samples with paired DNA and RNA sequencing results. Such gene expression integration will drive novel insights about the functional aspects of somatic coding and noncoding mutations in pediatric cancer. The innovative visualization of whole-genome sequencing data generated from 10K pediatric cancer patients on the St. Jude Cloud enables genomic discovery by scientists and clinicians through exploration of this unprecedented resource. Citation Format: Xin Zhou, Clay Mcleod, Scott Newman, Zhaoming Wang, Michael Rusch, Kirby Birch, Michael Macias, Jobin Sunny, Gang Wu, Jian Wang, Edgar Sioson, Shaohua Lei, Robert J. Michael, Aman Patel, Michael N. Edmonson, Stephen V. Rice, Andrew Frantz, Ed Suh, Keith Perry, Carmen Wilson, Leslie L. Robinson, Yutaka Yasui, Kim E. Nichols, Gregory T. Armstrong, James R. Downing, Jinghui Zhang. Visualize 10,000 whole-genomes from pediatric cancer patients on St. Jude Cloud [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3671.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3671
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 24 ( 2016-12-15), p. 7277-7289
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 24 ( 2016-12-15), p. 7277-7289
    Abstract: Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type–dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4–HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277–89. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-2100
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Abstract 6144: St. Jude Pediatric Brain Tumor Portal: Cloud-based resource for patient-derived orthotopic xenograft (PDOX) models of pediatric high-grade glioma, ependymoma, and CNS embryonal tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 6144-6144
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 6144-6144
    Abstract: Pediatric brain tumors comprise a distinct spectrum of diseases compared to adult brain tumors and are distinguished by their unique clinical and histopathological features, developmental context, mutation burden, and genomic, epigenomic, and transcriptomic alterations. Access to in vivo models that recapitulate pediatric brain tumors has been limited and inadequate to represent these heterogeneous diseases. Here we introduce the Pediatric Brain Tumor Portal (PBTP, pbtp.stjude.cloud), an open resource to access molecular characterization, including whole-genome sequencing, whole-exome sequencing, RNA-seq, and DNA methylome profiling, of patient-derived orthotopic xenograft (PDOX) models of pediatric brain tumors. The portal will host more than 70 models, which currently include pediatric High-Grade Glioma (pHGG), Medulloblastoma, Atypical Teratoid/Rhabdoid Tumors (AT/RT), Ependymoma, and Embryonal Tumors with Multilayered Rosettes (ETMR), and reflects close to ten years of effort to generate and extensively characterize in vivo models that recapitulate primary pediatric brain tumors. PBTP is a database-driven and user-friendly platform that enables multi-omics views of PDOX and matched patient tumor and germline samples at multiple levels to help identify appropriate lines for studies of tumorigenesis or preclinical testing. To evaluate the representation of different molecular features within a disease subgroup, we implemented various visualization tools for searching and comparing somatic mutations, gene expression profiles, and methylation groups of our models and matched patient tumors. Details for each tumor including de-identified clinical data, histology, growth characteristics, DNA methylation classification, mutation status, and copy number variations are also readily available for side-by-side comparison. Furthermore, in vitro chemical sensitivity profiling is presented for selected models with matched cell lines. Users can investigate genes of interest for single nucleotide variants, small insertions and deletions, copy number variations, gene fusions, and mRNA expression in PDOX and matched patient tumors. This portal has been integrated into the St. Jude Cloud platform, through which users can explore patient and PDOX sequencing data in the context of larger cohort data sets and download raw genomics data files. PBTP provides a platform to share PDOX models with in-depth genome/epigenome-wide characterization to support advances in basic and translational research in pediatric brain tumors. *co-first, #co-corresponding Citation Format: Paige S. Dunphy, Ke Xu, Darrell T. Gentry, Chen He, Kimberly Mercer, Xiaoyan Zhu, Kyle Smith, Brian Gudenas, Sarah Robinson, Junyuan Zhang, Lawryn H. Kasper, Chang-Hyuk Kwon, Laura D. Hover, Jon D. Larson, Nathaniel Twarog, Aksana Vasilyeva, Nedra Robison, Daniel Alford, Cynthia Williams, Anthony Woodard, Xin Zhou, Edgar Sioson, J. Robert Michael, Austyn Trull, Irina McGuire, Brandon McMahan, Swapnali Mohite, Ashok Boddu, Kirby Birch, Clay McLeod, Michael A. Dyer, Paul Klimo, Frederick A. Boop, Amar Gajjar, Christopher L. Tinkle, Giles Robinson, Brent A. Orr, Jason Chiang, Paul A. Northcott, Jinghui Zhang, Keith Perry, Gang Wu, Anang A. Shelat, Ed Suh, Martine F. Roussel, Suzanne J. Baker. St. Jude Pediatric Brain Tumor Portal: Cloud-based resource for patient-derived orthotopic xenograft (PDOX) models of pediatric high-grade glioma, ependymoma, and CNS embryonal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6144.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-6144
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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