bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4968: Tumor innate immunity primed by specific interferon stimulated endogenous retroviruses
Authors: Barbie David A. 
Published: August 2018

Abstract
Introduction: Tumor cell heterogeneity is a key determinant of cancer progression and drug resistance, which is often mediated by mesenchymal cell subpopulations. While these subclones can secrete growth factors, chemokines and cytokines, the immune signaling networks that fuel this pro-tumorigenic state remain incompletely defined. Elucidating what underlies this state would provide insights into tumor biology and inform clinical strategies to improve anti-cancer therapies.
Methods: Because of their well-defined nature, we used the phenotypically distinct H69M and H69AR Small Cell Lung Cancer (SCLC) mesenchymal subclones to uncover a novel mechanism of dysregulated innate immune signaling as compared with parental neuroendocrine H69 cells. Analysis of gene signatures across TCGA and CCLE databases, functional studies in additional cell lines, and ex vivo testing of patient-derived organotypic tumor spheroids (PDOTS) were conducted to determine the broader relevance across human cancers.
Results: We discovered a novel epigenetically regulated subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in mesenchymal cancer subpopulations. Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3'UTRs of certain interferon-inducible genes and silenced by EZH2. De-repression of these loci resulted in dsRNA generation following IFNγ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' LTR of the antisense ERV. We found that dsRNA sensing preferentially by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction across specific human tumors and cell lines is tightly associated with downregulation of chromatin modifying enzymes, including EZH2, a mesenchymal AXL positive cell state, and B2M and MHC class 1 antigen expression. SPARCS high tumors were marked by immune infiltration, but also exhibited multiple features of tumor
immune suppression. IFNγ treatment of PDOTS with de-repressed SPARCS markedly enhanced CXCL10 production and sensitized them to PD-1 blockade.
Conclusions: Together, these data unveil a novel subclass of ERVs whose de-repression triggers pathologic innate immune signaling in cancer, with potentially important implications for cancer immunotherapy.
Citation Format: David A. Barbie. Tumor innate immunity primed by specific interferon stimulated endogenous retroviruses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4968.
Abstract 4980: Regulating the regulator: Long noncoding RNAs in the p53 network in colorectal cancer
Authors: Chaudhary Ritu , Li Xiao Ling , Lal Ashish 
Published: August 2018

Abstract
Thousands of long noncoding RNA (lncRNA) genes are transcribed from the human genome, yet the biology of the vast majority remains to be investigated. To identify lncRNAs that could be important, we functionally integrate lncRNAs into tumor suppressor pathways, more specifically the p53 pathway. We identified and functionally characterized two intergenic nuclear-retained lncRNAs that we named PINCR (p53 induced noncoding RNA) and PURPL (p53-upregulated regulator of p53 levels). Our results show that both PINCR (Chaudhary et al, eLife, 2017) and PURPL (Li et al, Cell Reports, 2017), function as pro-survival p53-regulated genes during DNA damage and in mouse xenografts. Mechanistically, PINCR and PURPL mediate the effects of p53 in colorectal cancer (CRC) cells by regulating p53 itself or by modulating the expression of a subset of p53 targets via interactions with unique proteins in the nucleus. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced apoptosis to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets including BTG2, RRM2B and GPX1. Silencing these PINCR targets phenocopies the effect of loss of PINCR in response to DNA damage suggesting that they could be important downstream effectors of this lncRNA. Using CRISPR-Cas9-mediated knock-in of a single S1-tag at the 3'end of PINCR followed by an RNA pulldown approach that utilized endogenous S1-tagged PINCR, we found that PINCR associates with the enhancer region of these genes by binding to RNA-and DNA-binding protein Matrin 3 that, in turn, associates with p53. We show that PINCR is important for the recruitment of Matrin 3 to the enhancer region of these genes and for their complete p53-dependent induction after DNA damage. In addition, our unpublished data provide further insights on the molecular function of these lncRNAs in CRC. Collectively, our studies reveal critical roles of PINCR and PURPL in the p53 network and uncover unique modes by which lncRNAs can function.
Citation Format: Ritu Chaudhary, Xiao Ling Li, Ashish Lal. Regulating the regulator: Long noncoding RNAs in the p53 network in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4980.
Abstract 500: A p53/miR-30a/ZEB2 axis controls basal-like/triple-negative breast cancer aggressiveness
Authors: Damiano Valentina , Gennaro Alessandra di , Brisotto Giulia , Armellin Michela , Perin Tiziana , Zucchetto Antonella , Guardascione Michela , Spaink Herman P. , Doglioni Claudio , Snaar-Jagalska Ewa , Santarosa Manuela , Maestro Roberta 
Published: August 2018

Abstract
Inactivation of p53 plays a major role in the poor prognosis of basal-like /triple-negative breast cancers (TNBC). However, how p53 inactivation impinges upon TNBC aggressive phenotype is only partially defined. Here we report the identification of a novel axis involving p53, miR30a and ZEB2. We provide evidence that p53 affects the expression of ZEB2, a transcription factor involved in epithelial-mesenchymal transition (EMT), by relying on miR-30a. In particular, we found that p53 regulates miR-30a expression by direct promoter binding and that miR30a targets ZEB2. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and migration and that reduced miR-30a expression correlates with p53 inactivation and dismal prognosis in human breast cancers. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds a novel element to the complex network whereby p53 inactivation impinge upon tumor aggressiveness.
Citation Format: Valentina Damiano, Alessandra di Gennaro, Giulia Brisotto, Michela Armellin, Tiziana Perin, Antonella Zucchetto, Michela Guardascione, Herman P. Spaink, Claudio Doglioni, Ewa Snaar-Jagalska, Manuela Santarosa, Roberta Maestro. A p53/miR-30a/ZEB2 axis controls basal-like/triple-negative breast cancer aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 500.
Abstract 5006: Kit-dependent tissue resident macrophage progenitors drive cancer progression
Authors: Pathria Paulina , Takahashi Hideyuki , Kaneda Megan , Varner Judith A. 
Published: August 2018

Abstract
Macrophages play a key role in promoting tumor growth and resistance to therapy. Here we show that tissue-resident as well as bone marrow-derived macrophages play critical roles in promoting tumor growth. Tissue-resident macrophages were recently shown to originate in the yolk sac or fetal liver during embryogenesis; these cells self-maintain in post-natal tissues independent of hematopoietic stem cells. Tissue-resident macrophages and bone marrow-derived macrophages rapidly accumulate in tumors where they play independent roles in promoting tumor growth. Tissue-resident macrophages are CD11b+Gr1-F4/80hiCX3CR1hiCCR2-Ki67+ cells that accumulate in tumors independently of trafficking receptors. In contrast, bone marrow-derived CD11b+Gr1+F4/80loCX3CR1loCCR2+ macrophages accumulate in tumors in an integrin α4β1/αLβ2 and CCR2 or CXCR4-dependent manner. Gene expression studies show that tumor-associated tissue-resident macrophages are highly proliferative, immune-suppressive myeloid cells that are less proangiogenic than bone marrow-derived macrophages. Our studies show that tumor cells induce the expansion of tissue-resident macrophage progenitor cells by secreting stem cell factor and mCSF. Here we identify a Kit/KitL-dependent tissue-resident macrophage progenitor that is abundant in tumors but not in normal tissues. Notably, tumor growth and colony-forming activity are significantly inhibited in mice treated with SCF and Kit inhibitors. Tumors adoptively transferred with tissue-resident macrophage progenitor cells exhibited a significant growth advantage over control tumors. Furthermore, Kit inhibitors synergize with other immune therapy regimens to suppress tumor growth. Our studies show that tissue-resident macrophage progenitors promote aggressive tumor growth that can be targeted by Kit/SCF inhibition.
Citation Format: Paulina Pathria, Hideyuki Takahashi, Megan Kaneda, Judith A. Varner. Kit-dependent tissue resident macrophage progenitors drive cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5006.
Abstract 5016: A unique ex vivo drug evaluation model: 3D co-cultured system with tumor, stroma and blood microvessels
Authors: Takahashi Yuki , Tsukamoto Kei , Kitano Shiro , Irie Shinji , Matsusaki Michiya , Nagayama Satoshi , Katayama Ryohei , Shinozaki Eiji , Fujita Naoya 
Published: August 2018

Abstract
Background; Two dimensional single-layer culture still remains the preferred platform for most laboratory preclinical studies, although interaction between cancer and stromal cells has been well reported to be important in tumor progression and resistance against therapies. In order to mimic the patient tumor tissues, ex vivo model which recaptures the tumor microenvironment is required.
Methods; Layered 3D stromal tissues were produced by culturing normal human dermal fibroblasts (NHDFs) and human umbilical vein endothelial cells (HUVECs) coated with extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin. The layered 3D stromal tissues and overlaid tumors were morphologically characterized by HE stain, immunohistochemistry (IHC) and immunofluorescence (IF). Furthermore, drug sensitivity assays were conducted using popular colorectal cancer cell lines, and patient-derived cell lines (PDCs) established in the laboratory of Japanese Foundation for Cancer Research. Cancer cell viability was evaluated by fluorescent labeling, enzymatic dissociation and cell counting analysis. IF with cancer specific markers and imaging analyses were also performed.
Results; The 3D stromal tissues including CD31 positive luminal structure were multi-layered (approximately 20 layers), and formation of microvascular network was observed within several days. In comparison with 2D mono-culture or 3D mono/co-cultured spheroid model, decreased drug sensitivities were represented in our 3D co-cultured model. In the simultaneous treatment with cytotoxic anticancer agents and molecular targeted drugs, dose-responses were significantly different between the2D and 3D models.
Conclusion; We developed the layered 3D stromal tissue culture system including blood micro-vessels. Drug evaluation with the co-cultured tumors may reflect the drug sensitivity of cancer cells in vivo. Our unique 3D ex vivo model represents a valuable tool for drug development in a fully human cell and matrix microenvironment, and thus testing patient-derived cells and approved compounds also enable better prediction their efficacy.
Citation Format: Yuki Takahashi, Kei Tsukamoto, Shiro Kitano, Shinji Irie, Michiya Matsusaki, Satoshi Nagayama, Ryohei Katayama, Eiji Shinozaki, Naoya Fujita. A unique ex vivo drug evaluation model: 3D co-cultured system with tumor, stroma and blood microvessels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5016.
Abstract 5035: Identification of novel therapeutics of bladder cancer cells through upregulation of SPARC expression in using 2D cell cultures and 3D bladder organoids
Authors: Patel Chirayu M. , Ivan Cristina , Atala Anthony , Said Neveen 
Published: August 2018

Abstract
We have recently reported the tumor suppressor effect of SPARC in urinary bladder cancer. We have shown that the loss of SPARC in bladder cancer resulted accelerated bladder carcinogenesis and metastasis multiple pathways involving cell cycle deregulation, inflammation and angiogenesis. We have also reported that SPARC protein expression significantly decreased in the cancerous compartment in advanced human bladder cancer as well as in carcinogen-induced murine urothelial cancer. However, the mechanism of the downregulation of SPARC expression in cancer in general and in bladder cancer in particular is still unraveled. The purpose of our study is to identify therapeutic candidates as regulators of SPARC expression in bladder cancer. We developed an in vitro 3-D bladder model system “bladder organoids” that comprises the normal and cancerous urothelial cell, bladder smooth muscle cells, fibroblasts and endothelial cells. We differentially expressed fluorescent SPARC promoter reports in the cancerous and non-cancerous cells to screen for the differential expression of SPARC in each cell type using FDA-approved and natural product drug libraries and to determine the cytotoxicity on cancerous vs non-cancerous cells. Real time monitoring of changes in SPARC expression was done by measuring fluorescence intensity using IncuCyte® ZOOM and InCell Analyzer 1000 Live Imaging Analysis Systems. We identified drugs that consistently exhibited dose-dependent augmentation or down-regulation of SPARC expression in cancer cells. Our screens using the identified novel up-regulators of SPARC expression that differentially reduce the viability of cancer cells and spare non-cancer cells in the organoids. Our efforts produced a platform that mimics bladder cancer microenvironment that can be adapted for throughput screening for targeted personalized therapies.
Citation Format: Chirayu M. Patel, Cristina Ivan, Anthony Atala, Neveen Said. Identification of novel therapeutics of bladder cancer cells through upregulation of SPARC expression in using 2D cell cultures and 3D bladder organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5035.
Abstract 5036: Visualization of cancer-derived exosome-mediated angiogenesis in a layered 3D stromal tissue model
Authors: Kitano Shiro , Tsukamoto Kei , Morimura Rii , Irie Shinji , Shinozaki Eiji , Yamaguchi Kensei 
Published: August 2018

Abstract
Background: Exosomes are small vesicles of sizes ranging from 30 to 150 nm that originate from the endosomal luminal membrane and are constantly released by fusion with cell membranes. Several studies have revealed that exosomes play an important role in mediating local and systemic cellular communication through the transmission of nucleic acid materials and information in the form of proteins. Here, we demonstrated a unique layered 3D stromal tissue model of visualization of promoting angiogenesis by exosomes in colorectal cancer (CRC) patients.
Method: The CRC specimens of exosome were obtained from 7 patients in stage IV. Isolation of total exosome was performed according to standard procedure by ultracentrifuge. Layered 3D stromal tissue model was constructed with human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts. Cells were aggregated by heparin and collagen to suspension under cationic condition. The cell suspension was seeded to transwell inserts membrane at a density of 2×106. Media were changed after 24h, and serum, exosome or supernatant after ultracentrifuge of serum (SAUS) was added to the 3D stromal tissue after 6 days. The isolated exosomes were diluted with an equal volume of PBS buffer to the serum sample. After cultivation, the tube formation of HUVEC was stained with Immunofluorescence, and the degree of hypervascularity was compared with healthy volunteers.
Result: Except for one serum specimen, hypervascularization was observed in the 3D stromal tissue model in an additive-dependent manner. Especially when exosome was added, hypervascularization was observed in the layered 3D stromal tissue model more efficiently than serum in all specimens (see Table). Interestingly, the frequency of hypervascularization was drastically reduced in the SAUS.
Conclusion: Our data encourage that this layered 3D stromal tissue model may be applicable to cancer diagnosis using exosomes from CRC patients.
Table. Frequency of hypervascularization by exosomes derived from CRC5μl10μl50μlExosome5/7 (71.4%)7/7 (100.0%)7/7 (100.0%)Serum4/7 (57.1%)6/7 (85.7%)6/7 (85.7%)SAUS1/7 (14.3%)0/7 (0.0%)0/7 (0.0%)
Citation Format: Shiro Kitano, Kei Tsukamoto, Rii Morimura, Shinji Irie, Eiji Shinozaki, Kensei Yamaguchi. Visualization of cancer-derived exosome-mediated angiogenesis in a layered 3D stromal tissue model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5036.
Abstract 5053: Mlh1 deficiency increases the risk of hematopoietic malignancies post low- and high-LET radiation exposure
Authors: Patel Rutulkumar , Gerson Stanton L. , Welford Scott M. 
Published: August 2018

Abstract
Introduction/Aim: Natural sources of radiation in space include galactic cosmic rays (GCR), solar energetic particles and trapped energetic particles in a planetary magnetic field. These sources are difficult to shield, thus posing significant health risks to astronauts on long-term inter-planetary missions. During space travel, genomic instability is a major concern where astronauts are exposed to potent sources of ionizing radiation, namely GCR consisting of high energy and charged atomic nuclei. In particular, hematopoietic stem cells (HSCs) are susceptible to internal and external stresses that threaten the integrity of the cell, and accumulation of damage can lead to HSCs dysfunction and oncogenesis. Recent data has demonstrated that humans accumulate microsatellite instability with acquired loss of MLH1 protein in HSCs as a function of age. Therefore, we hypothesized that high-LET (linear energy transfer) radiation characteristic of the GCR that will confront astronauts on space missions will damage HSCs and contribute to induction and progression of hematopoietic malignancies. Methods: To study this hypothesis, we employed a DNA mismatch repair deficient mouse model (Mlh1+/-) to study the effects of low-LET γ-ray vs high-LET 56Fe ion radiation on HSCs of potential astronaut population. In vitro colony forming unit assays and in vivo complete blood count (CBC) plus competitive repopulation assays were carried out to understand harmful impact of radiation and Mlh1 deficiency on HSCs functions. In addition, mice were followed up to 18 months post irradiation to observe HSC malignancies in Mlh1+/+ and Mlh1+/- mice. Results: HSC short- and long-term functional assays showed defects in HSCs/HPCs function caused by irradiation, but not depending on Mlh1 status. CBC 5 and 9 months post irradiation demonstrated no impact of irradiation or Mlh1 status on HSC differentiation. However, 56Fe-ion irradiated Mlh1+/- mice showed a significant higher incidence of lymphomagenesis compared to γ-rays irradiated and sham-irradiated Mlh1+/- mice. In addition, immunohistochemistry analysis of lymphomas displayed significant higher incidence of T-cell rich B-cell lymphomas. Conclusion: Thus, the data show that MMR defects in HSCs leads to sensitization to radiation induced hematopoietic malignancy, and that radiation quality effects exacerbate the sensitivity. The findings could have profound effects on astronaut screening and designing better mitigators for space missions.
Citation Format: Rutulkumar Patel, Stanton L. Gerson, Scott M. Welford. Mlh1 deficiency increases the risk of hematopoietic malignancies post low- and high-LET radiation exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5053.
Abstract 5067: b1-Integrin promotes inflammatory cytokine-induced vascular leakage
Authors: Kiss Elina A. , Hakanpää Laura , Jacquemet Guillaume , Miinalainen Ilkka , Lerche Martina , Guzman Camilo , Mervaala Eero , Eklund Lauri , Ivaska Johanna , Saharinen Pipsa 
Published: August 2018

Abstract
Increased capillary leakage is a potentially life-threatening condition associated with sepsis and cytokine release syndrome (CRS) that develops as a side effect of novel chimeric antigen receptor (CAR) T-cell cancer immunotherapies. CRS and sepsis are characterized by immune activation, resulting in elevated circulating levels of inflammatory cytokines including IL-6 and IL-1β, and thrombin that promote vascular leakage and the development of hypovolemic shock and multiorgan failure. However, molecular mechanisms behind capillary leakage remain unknown, and importantly, targeted approaches for the management of capillary leakage are limited. Here, we found that β1-integrin acts as a critical universal mediator of endothelial permeability induced by various inflammatory agents, including LPS, IL-6, IL-1β and thrombin. In a mouse model of LPS-induced systemic inflammation, resulting in increased inflammatory cytokine production and vascular leakage, function blocking antibodies against β1-integrin prevented vascular leakage and improved integrity of vascular endothelium, leading to protection from LPS-induced cardiac failure. β1-integrin blocking antibodies were effective in reducing vascular leakage even when administered after the onset of systemic inflammation and increase in the serum levels of IL-6, IL-1β and TNF-α. By using an in vitro model, we found that inflammatory agents generated mechanical stress, in a β1-integrin dependent manner, leading to endothelial cell contractility and permeability. Conclusively, our data indicates that β1-integrin promotes vascular leakage in inflammation, and that targeting this mechanism may have therapeutic utility for vascular stabilization in CRS and capillary leak syndromes associated with immune activation and systemic inflammation.
Citation Format: Elina A. Kiss, Laura Hakanpää, Guillaume Jacquemet, Ilkka Miinalainen, Martina Lerche, Camilo Guzman, Eero Mervaala, Lauri Eklund, Johanna Ivaska, Pipsa Saharinen. b1-Integrin promotes inflammatory cytokine-induced vascular leakage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5067.