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  • American Association for Cancer Research (AACR)  (6)
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  • American Association for Cancer Research (AACR)  (6)
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  • 1
    Online Resource
    Online Resource
    Abstract 3956: Differential miR-141 expression in primary cultured human breast cancer epithelium (PCHBCEs) and normal adjacent part epithelium (PCHBNEs) correlates with tumor suppressor protein tyrosine phosphataseγ (PTPγ)
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3956-3956
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3956-3956
    Abstract: MicroRNAs (miR) have been shown to be extensively involved in tumorigenesis by post-transcriptional inhibition of oncogenes and/or tumor-suppressor genes. The purpose of our study is to investigate the difference in miRNA expression between cancer epithelium and epithelium from normal breast adjacent tissues. The clinical samples were procured from the Tissue Procurement Program at the Ohio State University Comprehensive Cancer Hospital from breast cancer patients who underwent partial or complete mastectomy. The miRNA profiling for one pair of PCHBCEC and PCHBNEC from the same patient was carried out, and the difference of miRNA expression and potential target genes were further verified by realtime qPCR in 7 pairs of clinical samples. The miRNA profiling showed that 24 miRNAs (let-7a, let-7c, let-7f, let-7g, miR-24, miR-28, miR-29a, miR-29c, miR-30a-5p, miR-30d, miR-92, miR-125a, miR-126*, miR-132, miR-135a, miR-135b, miR-137, miR-141, miR-182, miR-200c, miR-339, miR-365, miR-425-5p, miR-391, p & lt;0.05) are statistically up-regulated in cancer while only 1 miRNA (miR-221) is down-regulated. Based on the magnitude of change and predicted target, we selected miR-141 for further validation. Compared with its normal adjacent counterpart, 4 PCHBCECs had lower miR-141 while 2 were up-regulated and 1 unaltered. Further validation on gene expression of the samples confirmed the negative correlation of miR-141 with its putative target PTPγ. Our comparison of PCHBCECs and PCHBNECs under the same genetic background demonstrated a distinct expression of miRNAs. The dysregulation of miR-141 was shown to result in modulation of the potential tumor-suppressor gene PTPγ which might have an impact on the etiological process of tumor lesion and discriminate cancer epithelial cells from their surrounding normal breast epithelial compartments. Our results implicate that miR-141 might serve as molecular biomarker for therapy of human breast cancer patients. (Supported by NIH R01 Grant ES 015212). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3956. doi:10.1158/1538-7445.AM2011-3956
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3956
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 7 ( 2020-07-01), p. 1058-1077
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 7 ( 2020-07-01), p. 1058-1077
    Abstract: Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53−/− PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. Significance: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components. See related commentary by Carr and Fernandez-Zapico, p. 910. This article is highlighted in the In This Issue feature, p. 890
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-0597
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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  • 3
    Online Resource
    Online Resource
    Faecalibacterium prausnitzii abrogates intestinal toxicity and promotes tumor immunity to increase the efficacy of dual CTLA-4 and PD-1 checkpoint blockade
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research ( 2023-08-21)
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), ( 2023-08-21)
    Abstract: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, their application is limited by the occurrence of immune-related adverse events. The gut microbiota plays important roles in the response to and toxicity of immunotherapy, and Faecalibacterium prausnitzii (F. prausnitzii) has been shown to possess immunomodulatory potential. Here, we found that patients receiving ICIs who developed colitis had a lower abundance of F. prausnitzii. In vivo, immunocompetent mice administered with dextran sodium sulfate and immunodeficient NSG mice with human peripheral blood mononuclear cell transfer were treated with ICIs to study ICI-induced colitis. Dual CTLA-4 and PD-1 blockade exacerbated autoimmune colitis, activated an inflammatory response, and promoted myeloid cell infiltration, with higher percentages of macrophages, dendritic cells, monocytes, and neutrophils. F. prausnitzii administration mitigated the exacerbated colitis induced by ICIs. Concomitantly, F. prausnitzii enhanced the anti-tumor immunity elicited by ICIs in tumor-bearing mice while abrogating colitis. In addition, administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. F. prausnitzii abundance was reduced in mice that developed ICI-associated colitis. Together, this study shows that F. prausnitzii administration ameliorates ICI-induced colitis, reshapes the gut microbial composition, and enhances the anti-tumor activity of immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-23-0605
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 1 ( 2016-01-01), p. 80-95
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 1 ( 2016-01-01), p. 80-95
    Abstract: The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo–YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP–TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5–CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. Significance: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo–YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5–CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival. Cancer Discov; 6(1); 80–95. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-0224
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2607892-2
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  • 5
    Online Resource
    Online Resource
    Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 7 ( 2022-07-06), p. 1690-1701
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 7 ( 2022-07-06), p. 1690-1701
    Abstract: The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non–small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC. Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-21-1486
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2607892-2
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  • 6
    Online Resource
    Online Resource
    Abstract A28: USP21 promotes stemness of pancreatic cancer cells and bypass of KRAS extinction
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Research Vol. 18, No. 5_Supplement ( 2020-05-01), p. A28-A28
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 5_Supplement ( 2020-05-01), p. A28-A28
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths, with an estimated 44,330 deaths per year in the United States alone. Deubiquitinases play fundamental roles in maintenance of cellular homeostasis, and deregulation of ubiquitin-specific proteases (USPs), the largest group of deubiquitinases, has been reported in multiple cancer types. In particular, we found that USP21 is amplified in 22% of PDAC cases in the patient dataset from the University of Texas Southwestern Medical Center, and it is the most frequently deregulated USP. However, little is known about the role of USP21 in PDAC. To examine biologic function of USP21 amplification in PDAC, we employed a novel “iKPC” mouse model, harboring tetO-LSL-KrasG12D (a transgenic allele with doxycycline-controlled tet-ON system regulating transcriptionally activated KRASG12D), ROSA26-LSL-rtTA, p53L/+ and p48Cre. We induced overexpression of USP21 in PDAC cells isolated from iKPC mice and found that USP21 promotes iKPC pancreatic tumor growth in vivo and drives KRAS-independent pancreatic tumor growth after blockage of KRAS expression. USP21 has a nuclear export signal and shuttles between the nucleus and cytoplasm. By modulating its subcellular localization, we discovered different functions of USP21 in supporting pancreatic cancer growth. Specifically, the nuclear function of USP21 supports pancreatic tumor growth by increasing tumor cell stemness via enhanced activation of the Wnt/beta-catenin signaling pathway. We showed that USP21 directly regulates proteasome pathway-dependent degradation of TCF7 protein. The cytoplasmic function of USP21 stimulates tumor cells to bypass KRAS extinction via MARK3, which phosphorylated its substrates and blocked their function by generating 14-3-3 binding sites. We found that MARK3 interacts with and is deubiquitinated by USP21. Knockdown of Ptpn3, a reported substrate of MARK3, increased protein level of PDGFRA, overexpression of which bypassed KRAS extinction. Moreover, we showed that inhibition of PDGF receptor pathway impairs KRAS-independent PDAC tumor growth driven by USP21 in vivo. Thus, our work demonstrated distinct oncogenic functions of USP21 in the presence and absence of KRAS signaling in PDAC, suggesting that KRAS-mutant PDAC patients with USP21 amplification may become resistant to KRAS inhibition. Citation Format: Pingping Hou, Xingdi Ma, Jeffery Ackroyd, Jianhua Zhang, Shan Jiang, Alan Y. Wang, Ronald A. DePinho. USP21 promotes stemness of pancreatic cancer cells and bypass of KRAS extinction [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A28.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.RAS18-A28
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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