tbuckley/cabot-search huggingface dataset:
Abstract 2844: Identification of genes associated with pancreatic cancer metastasis by genome-wide CRISPR Cas9 screening
Authors: Youjia Li, Huiyi Feng, Guangjie Liu, Chi Hin Wong, Chi Han Li, Yangchao Chen
Journal: Cancer Research (2017)

Abstract Pancreatic cancer is an extremely lethal cancer with a 5-year survival rate of 7%. One major reason why pancreatic cancer is hard to treat is its metastasis nature. Genes that related to the tumorigenesis and progression of pancreatic cancer were identified after decades of efforts. Several researches had revealed that pancreatic cancer originated from the successive accumulation of gene mutations, especially KRAS2, CNKD2A, TP53 and SMAD4. However, little is known about genes that regulate pancreatic cancer metastasis. Here we used a genome wide CRISPR Cas9 screening to identify the gene(s) associated with the metastasis of pancreatic cancer. We transduced pancreatic cancer cell line with lentivirus-based genome wide CRISPR sgRNA library to establish mutated cell library, and orthotopically injected the cell library into nude mice and waited for primary tumor growth and metastasis, then collected primary and metastatic tumors after several months. By next generation sequencing and analysis, we identified some gene candidates which may play important roles on pancreatic cancer metastasis. Note: This abstract was not presented at the meeting. Citation Format: Youjia Li, Huiyi Feng, Guangjie Liu, Chi Hin Wong, Chi Han Li, Yangchao Chen. Identification of genes associated with pancreatic cancer metastasis by genome-wide CRISPR Cas9 screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2844. doi:10.1158/1538-7445.AM2017-2844
Abstract 1968: A novel mechanism of metastasis: Extracellular ATP promotes invasion and metastasis independent of purinergic receptor signaling
Authors: Yanyang Cao, Xuan Wang, Xiaozhuo Chen
Journal: Cancer Research (2017)

Abstract Cancer is one of the top deadliest diseases in the US and worldwide. Metastasis, the dissemination of cancer cells from the primary tumors to distant organs, is responsible for 90% of solid tumor-related deaths. Tumor invasion and metastasis is a multistep process in which loss of cell-cell adhesion, increased proteolysis, and cell motility has been shown to be critical steps. Extracellular ATP is potentially a very important factor involved in tumor invasion and metastasis because both cell detachment and migration require energy, which is known to be mainly provided by ATP. Recent studies have indicated that the extracellular microenvironment of tumors contains much higher concentrations of ATP than normal tissues of the same cell origins. Our recent studies demonstrated that extracellular ATP is taken up by cancer cells through macropinocytosis and other endocytosis and promotes cancer cell growth, survival, and drug resistance (1-3). Based on all these, we hypothesized that extracellular ATP (eATP) plays critical roles in the regulation of tumor cell detachment, motility, invasion and tumor metastasis initiation. It was previously shown that ATP-induced purinergic receptor (PR) signaling is involved in metastasis. Our hypothesis is different in that eATP also mediates invasion and metastasis independent of PR signaling. Various bioassays were used in human non-small cell lung cancer (NSCLC) A549 cells to test our hypothesis. Our results show that eATP treatment led to a substantially increased number of floating cancer cells, and these cells were viable and formed clones in a clonogenic assay. This indicates that eATP induces cancer cell detachment. Moreover, treatment of eATP also induces cell migration in cell wounding and Transwell migration assays. In vitro invasion assay showed that eATP induced a dose-and time-dependent increase in the invasive capacities of the A549 cells. Western blot analysis indicates that eATP treatment reduced the expression of cell-cell adhesion molecule E-cadherin. PR inhibitors only slightly attenuated these effects. All these suggest novel ATP mechanisms independent of the PR signaling that are unreported before and imply novel targets for inhibiting/preventing metastasis. References 1. Qian et al. Cancer Letters 351; 242-251 (2014). 2. Chen, Qian, and Wu. Free Radical Biol Med 79; 253-263 (2015) 3. Qian et al. Mol Cancer Res 14(11); 1087-1096 (2016) Citation Format: Yanyang Cao, Xuan Wang, Xiaozhuo Chen. A novel mechanism of metastasis: Extracellular ATP promotes invasion and metastasis independent of purinergic receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2017-1968
Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence
Authors: Pierre-Eric Lutz, Arnaud Tanti, Alicja Gasecka, Sarah Barnett-Burns, John J. Kim, Yi Zhou, Gang G. Chen, Marina Wakid, Meghan Shaw, Daniel Almeida, Marc-Aurele Chay, Jennie Yang, Vanessa Larivière, Marie-Noël M’Boutchou, Léon C. van Kempen, Volodymyr Yerko, Josée Prud’homme, Maria Antonietta Davoli, Kathryn Vaillancourt, Jean-François Théroux, Alexandre Bramoullé, Tie-Yuan Zhang, Michael J. Meaney, Carl Ernst, Daniel Côté, Naguib Mechawar, Gustavo Turecki
Journal: American Journal of Psychiatry (2017)

Child abuse has devastating and long-lasting consequences, considerably increasing the lifetime risk of negative mental health outcomes such as depression and suicide. Yet the neurobiological processes underlying this heightened vulnerability remain poorly understood. The authors investigated the hypothesis that epigenetic, transcriptomic, and cellular adaptations may occur in the anterior cingulate cortex as a function of child abuse.Postmortem brain samples from human subjects (N=78) and from a rodent model of the impact of early-life environment (N=24) were analyzed. The human samples were from depressed individuals who died by suicide, with (N=27) or without (N=25) a history of severe child abuse, as well as from psychiatrically healthy control subjects (N=26). Genome-wide DNA methylation and gene expression were investigated using reduced representation bisulfite sequencing and RNA sequencing, respectively. Cell type-specific validation of differentially methylated loci was performed after fluorescence-activated cell sorting of oligodendrocyte and neuronal nuclei. Differential gene expression was validated using NanoString technology. Finally, oligodendrocytes and myelinated axons were analyzed using stereology and coherent anti-Stokes Raman scattering microscopy.A history of child abuse was associated with cell type-specific changes in DNA methylation of oligodendrocyte genes and a global impairment of the myelin-related transcriptional program. These effects were absent in the depressed suicide completers with no history of child abuse, and they were strongly correlated with myelin gene expression changes observed in the animal model. Furthermore, a selective and significant reduction in the thickness of myelin sheaths around small-diameter axons was observed in individuals with history of child abuse.The results suggest that child abuse, in part through epigenetic reprogramming of oligodendrocytes, may lastingly disrupt cortical myelination, a fundamental feature of cerebral connectivity.
Abstract 5195: Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells
Authors: Francesca Amoroso, Adam Pickard, Alice McNaney, Rohinton Tarapore, Joshua E. Allen, Ian G. Mills
Journal: Cancer Research (2017)

Abstract Prostate cancer is the highest incidence non-cutaneous cancer in men, and a significant cause of cancer mortality. Localized disease is treated with surgery or radiotherapy and whilst androgen deprivation therapy can extend survival in the subset of cases that progress, metastatic disease is incurable. We have found that oncogenic drivers of prostate cancer, as well as therapy, lead to changes in the activation of prostate cancer cell stress signaling pathways and in particular the unfolded protein response (UPR). We have previously reported that the androgen receptor sustains the cytoprotective activity of the IRE1-XBP1 arm of the UPR and represses the activation of the PERK-ATF4 arm. We showed that treating prostate cancer cells with radiation leads to the activation of all three arms of the UPR, culminating in treatment resistance in surviving cells. In this study we assess whether the activation of the UPR in response to radiation mirrors the immunogenic/inflammatory response, which is known to occur in an initially acute apoptotic phase before resolving to a chronic sustainable level. Further we have evaluated the impact of combining radiation with ONC201, a novel anti-cancer small molecule in clinical trials that is an activator of the UPR, on the viability of prostate cancer. We find that ONC201 has a delayed cytotoxic effect as a single agent, with the impact on viability occurring from 72 hours onwards at low microMolar concentrations. However activation of multiple arms of the UPR occurs earlier and is detectable at 24 hours for ATF4, ATF6 and IRE1-XBP1 at the protein/mRNA levels. This time difference creates a window in which to introduce sequential administration of radiation to test ONC201 as a primer for cytotoxic response radiation. We have undertaken this work in a panel of cell-lines (PC3, DU145 and AR-expressing cell-lines) in which we have also knocked down key regulators (PERK, IRE1, CHOP) of separate arms of the UPR. This represents the first in vitro study to characterise the impact of ONC201 on the radiation-responsiveness of prostate cancer cells. Citation Format: Francesca Amoroso, Adam Pickard, Alice McNaney, Rohinton Tarapore, Joshua E. Allen, Ian G. Mills. Modulating the UPR using the impridone ONC201 to change the impact of radiation on prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2017-5195
Abstract 917: CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages
Authors: Jae-Il Choi, Jin Hur, Hwan Lee, Pniel Nham, Cheong-Whan Chae, Young-Eun Choi, Taewan Kim, Ga-Young Lee, Sung Hee Baek, Hyo-Soo Kim
Journal: Cancer Research (2017)

Abstract Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 (CD82 hereafter) in niche-mediated LT-HSC maintenance. We found that CD82 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82-/- mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-b1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC+ BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche. Finally, we hope that further development of our study will allow us to improve leukemia treatment by awakening not only “good” stem cells to keep beneficial stem cell functions, but also “bad” stem cells (e.g. cancer stem cells) in order to increase the sensitivity to treatment and avoid relapse. Citation Format: Jae-Il Choi, Jin Hur, Hwan Lee, Pniel Nham, Cheong-Whan Chae, Young-Eun Choi, Taewan Kim, Ga-Young Lee, Sung Hee Baek, Hyo-Soo Kim. CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 917. doi:10.1158/1538-7445.AM2017-917
Abstract 2695: Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis
Authors: Asmaa El-Kenawi, Jasreman Dhillon, Arig Ibrahim-Hashim, Dominique Abrahams, Shari Pilon-Thomas, Brian Ruffell, Robert Gatenby, Robert Gillies
Journal: Cancer Research (2017)

Abstract Insufficiency in tumor perfusion and high rate glycolysis combine to reduce the pH of tumor microenvironment. In a TRAMP model of prostate cancer, we had shown that carcinogenesis is associated with increasing acidification of the microenvironment and that neutralization of this acidity can prevent cancer emergence or metastases. Carcinogenesis in the TRAMP model is also associated with increased fibrosis and immune cells infiltration. We thus sought to determine if fibrosis drives immune infiltration in early tumorigenesis or vice-versa; and whether this dynamics is affected by tumor acidity. To investigate this, we harvested prostates from TRAMP mice or their matching non-transgenic controls at different time points and stained serial prostate tissue sections with F4/80 (macrophages), SMA (cancer-associated fibroblasts, CAFs), and Masson’s Trichome (collagen). Quantitative image analysis reveals that increase in fibrosis occur prior to macrophage infiltration and that both events preceded tumor development. However, the relative amount of collagen fibers was unchanged across all time points. Notably, neither fibrosis nor macrophage infiltration occurred in mice treated with buffer, suggesting an involvement of acidity in this immune stromal interactions. Interestingly, macrophages isolated from latter time points in the untreated group as well as macrophages co-cultured with prostate tumor cells at acidic pH, possessed an M2-like phenotype by expressing immunosuppressive genes (e.g. Arginase 1, Arg1) and a range of scavenging receptors (e.g. mannose receptor, Cd206), as well as releasing more angiogenic factors (e.g. VEGF and MMPs). Similar results were recapitulated when M2 macrophages were stimulated at acidic pH by showing enhanced Cd206 and Arg1 expression. On the functional level, macrophages activated at acidic pH had a higher ability to uptake fluorescently labelled ovalbumin and collagen, as examples of mannosylated ligands that prevail the fibrotic microenvironment. In summary, these results suggest that tumor acidity may promote fibrosis, with subsequent macrophage infiltration and phenotypic switching, leading to increased collagen turnover. It is suspected that this extracellular matrix remodeling may be permissive for tumor progression. Citation Format: Asmaa El-Kenawi, Jasreman Dhillon, Arig Ibrahim-Hashim, Dominique Abrahams, Shari Pilon-Thomas, Brian Ruffell, Robert Gatenby, Robert Gillies. Role of tumor generated acidity in immune stromal interactions during prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2695. doi:10.1158/1538-7445.AM2017-2695
Abstract 2781: Exosomal Del-1 as a potent diagnostic marker for breast cancer: A prospective cohort study
Authors: Soo Jung Lee, Jeeyeon Lee, Yee Soo Chae, Jin Hyang Jung, Ho Yong park, Moon-Chang Baek, Pyong-Gon Moon
Journal: Cancer Research (2017)

Abstract Background: We previously demonstrated a diagnostic role of exosomal del-1 with two separated groups of breast cancer patients. In the current study, therefore, we aimed to confirm the diagnostic role in a prospective study with breast cancer by measuring plasma exosomal del-1 before and after surgery. Patients and methods: To identify the optimal time of sampling after surgery, serial blood at day 1, 3, 5, and 7 after surgery was collected from 22 patients with early breast cancer. Thereafter, One hundred fifteen patients with breast cancer who underwent curative surgery were enrolled in the prospective cohort study to compare difference in plasma exosomal del-1 measured by ELISA at the time of diagnosis and post-surgery. Results: Among all 22 patients for optimal sampling time after surgery, exosomal del-1 was higher than 0.5 at the time of diagnosis and then normalized at POD1. Among 115 patients for the confirmatory set, 109 (94.8%) patients showed a normalization of del-1 lower than 0.5 after surgery and 10 patients showed del-1&amp;gt; 0.4 . Median f/u duration of 22 months, 9 patients experienced relapse (4 locoregional and 5 distant), where 3 out of 6 in high group (&amp;gt;0.5), and 2 out of 4 in borderline group (0.4-0.5), and 4 out of 105 in normalized group (&amp;lt;0.4). In particular, patients who relapsed in higher del-1 group showed relatively earlier relapse compared to lower del-1 group. Conclusion: In a prospective cohort study, we confirmed that exosomal del-1 has a potent diagnostic role in breast cancer. Furthermore, del-1 was also identified to dramatically decrease after curative surgery. Our current findings suggest its potential prognostic role as well as diagnostic role in breast cancer patients. Changes of Exosomal Del-1 level between baseline and after-surgery (n=115)sampling timebaselineafter surgeryp-value(paired t-test)Del-1 (mean±SD)1.237±0.4530.188±0.124&amp;lt;0.001 Citation Format: Soo Jung Lee, Jeeyeon Lee, Yee Soo Chae, Jin Hyang Jung, Ho Yong park, Moon-Chang Baek, Pyong-Gon Moon. Exosomal Del-1 as a potent diagnostic marker for breast cancer: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2781. doi:10.1158/1538-7445.AM2017-2781
Abstract LB-123: Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers
Authors: Ryohei Katayama, Miho J. Fuse, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita
Journal: Cancer Research (2017)

Abstract Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small-cell lung cancer, and colorectal cancer. Although there are currently no clinically available inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKIs), such as entrectinib and LOXO-101, are in clinical trials. To identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance, we examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Then, acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea (ENU) mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. After identifying the resistance mechanisms, we performed drug screening with small-molecular inhibitors to overcome the resistance. As the results, we identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R. As a result of drug screening, we found that cabozantinib and a few TKIs effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or LOXO101. Furthermore, cabozantinib with an insulin growth factor receptor type 1 (IGF1R) inhibitor such as OSI906 could overcome bypass pathway-mediated resistance. Thus, in this study, we developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement. In addition, we found drugs and a combination therapy to overcome the identified resistance to NTRK1-TKI. Citation Format: Ryohei Katayama, Miho J. Fuse, Tomoko Oh-hara, Hayato Ogura, Naoya Fujita. Identification of the molecular mechanisms of resistance to NTRK inhibitors and the potential therapeutic strategies in NTRK1-rearranged cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-123. doi:10.1158/1538-7445.AM2017-LB-123
Abstract 2218: Quantitative multiplex analysis of immune checkpoint protein expression in circulation and in the tumor microenvironment
Authors: Wen-Rong Lie, Jehangir Mistry
Journal: Cancer Research (2017)

Abstract Immune checkpoint inhibitors have been proven to be an effective method in improving antitumor immune response. Many immune checkpoint proteins are expressed as soluble forms in circulation and in the tumor and tumor microenvironment. Here we report the development of bead-based Luminex multiplex assays for the quantitative profiling of co-inhibitory and co-stimulating immune checkpoint proteins CTLA-4, PD-1, TIM-3, LAG-3, HVEM. GITRL, BTLA, CD27, CD28, CD40, GITR, PD-L1, B7-1/CD80, B7-2/CD86, and ICOS. In order to explore the use of soluble immune checkpoint proteins as putative cancer biomarkers, we used these multiplex assays to measure checkpoint protein levels in serum samples from breast cancer patients, colon cancer patients, and a corresponding set of normal serum samples. Analysis of the soluble checkpoint protein signatures generated from this multiplex approach revealed a significantly elevated level of soluble TIM-3 protein in the breast cancer serum samples and in the colon cancer serum samples compared to the healthy serum controls (p&amp;lt;0.001). In addition, we analyzed the immune checkpoint protein expression profiles in lysates of tumor and adjacent normal tissues from 3 patients with metastatic breast cancer and 2 patients with colorectal cancer. Differential expression of multiple checkpoint proteins, including BTLA, CD27, TIM-3, HVEM, CD40, GITR, LAG3, CTLA-4, B7-1, PD-L1, or ICOS, were detected in these matched lysates, indicating the roles and complexity of checkpoint proteins in tumor microenvironment. In summary, our results demonstrate that the multiplex assays we developed are useful research tools for the simultaneously quantitation of immune checkpoint proteins, as well as its potential application in cancer biomarker discovery and translational research in cancer immunotherapy. Citation Format: Wen-Rong Lie, Jehangir Mistry. Quantitative multiplex analysis of immune checkpoint protein expression in circulation and in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2218. doi:10.1158/1538-7445.AM2017-2218
Abstract 15230: Depression is a Stronger Risk Factor for Obstructive Coronary Artery Disease and Major Cardiovascular Events in Young Women than Men and Older Women
Authors: Amit J Shah, Danny Eapen, Riyaz Patel, Ian Neeland, Dee Anderson, Pankaj Manocha, Suliman Alradawi, Ibrahim Kassas, Ravi Avati Nanjundappa, Emir Veledar, Arshed Quyyumi, Viola Vaccarino
Journal: Circulation (2011)

Introduction: Depression is a cardiovascular risk factor that is highly prevalent in young women, a group that also shows a disproportionately increased risk of adverse events after an acute MI. We...