bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 379: Myeloperoxidase-produced HOCl is a paracrine effector linking myeloid cells to NF-κB signaling in melanoma, mediating anti-tumor responses during early melanoma progression
Authors: Liu Tracy W. , Gammon Seth T. , Yang Ping , Fuentes David T. , Piwnica-Worms David 
Published: September 2020

Abstract
The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity and the microbicidal activities of phagocytes, while also impacting the pathogenesis of many disorders, including cancer. Upon MDC activation, MPO is secreted into phagosomes, catalyzing the production of hypochlorous acid (HOCl). HOCl is a potent chlorinating oxidant with significant biological effects, but the mechanisms by which HOCl impacts cancer growth remain unresolved. Herein, we demonstrate that the myeloid lineage-restricted MPO-HOCl system has anti-tumor effects during early melanoma progression. Orthotopic melanomas grew slower in immuno-competent host mice wild type for MPO+/+ compared to syngeneic MPO-null (MPO-/-) animals. Using a specific and potent inhibitor of MPO, 4-aminobenzoic acid hydrazide (4-ABAH), melanoma tumor growth in MPO+/+ mice continuously administered 4-ABAH, pharmacologically mimicked the MPO-/- phenotype. Real-time intravital tumor imaging in vivo using skinfold window chamber animal models as well as live cell co-culture studies revealed a cell-cell proximity-dependent association between MDC-derived MPO activity and blockade of ligand-induced IκBα degradation in tumor cells. Real-time bioluminescent imaging and quantitative monitoring of the canonical NF-κB pathway was assessed in melanoma cells stably expressing bioluminescent reporters: a transcriptionally-activated NF-κB-promoter-driven Firefly luciferase (FLuc) reporter or a fusion reporter under the control of an NF-κB-responsive promoter fused to IκBα-FLuc reporter. HOCl was shown to directly inhibit IκB kinase (IKK) activity, thereby decreasing NF-κB transcriptional activation within melanomas, increasing circulating levels of the myeloid-attracting cytokines CXCL1 and CXCL5, enhancing local infiltration of CD8+ cytotoxic T cells, and dampening tumor growth. Overall, these data reveal a novel role for MDC-derived HOCl as a small molecule paracrine signaling factor that trans-inhibits IKK in melanoma cells, mediating anti-tumor responses during early tumor progression.
Citation Format: Tracy W. Liu, Seth T. Gammon, Ping Yang, David T. Fuentes, David Piwnica-Worms. Myeloperoxidase-produced HOCl is a paracrine effector linking myeloid cells to NF-κB signaling in melanoma, mediating anti-tumor responses during early melanoma progression [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 379.
Abstract 3833: Epigenetic regulation of cell state transitions and the therapeutic implications in breast cancer
Authors: Toh Li Ping , Loo Ser Yue , Tam Wai Leong 
Published: September 2020

Abstract
During cancer progression, cells would reversibly transit among different cell states that differ in their competence to contribute towards tumor growth, survival, and metastasis. The activation of epithelial-mesenchymal transition (EMT) program in cancer cells has often been attributed to enhanced tumorigenic potential and a gain of therapeutic resistance. We hypothesized that by promoting mesenchymal-epithelial transition (MET), the reverse process of EMT, it could induce a loss of tumorigenic potential and increase susceptibility to standard chemotherapeutics. As EMT is a dynamic and reversible process, epigenetic regulations such as histone modifications and DNA methylation are important in regulating and reprogramming the expression of EMT-responsive genes. Hence, we seek to understand how the epigenetic landscape is altered during transitions between cell states. To understand the molecular link between epigenetic regulations and cell state transitions in cancer cells, a high-throughput library screen on epigenetic modifiers was performed. Epigenetic modifying compounds that can induce MET in basal-like breast cancer cells were uncovered. In vitro and in vivo data demonstrate that compounds targeting the non-BET bromodomains were able to promote MET, induce a loss of stem-like properties, and decrease the tumorigenicity of basal-like breast cancer cells. Using various next-generation sequencing approaches, we also elucidated the mechanisms of how targeting non-BET bromodomains would regulate cell state transitions in breast cancers. While epigenetic therapies are effective in the treatment of hematological malignancies, its application in solid tumors is still limited. Here, we propose the possible use of an epigenetic MET inducer for differentiation therapy of the aggressive basal-like breast cancers.
Citation Format: Li Ping Toh, Ser Yue Loo, Wai Leong Tam. Epigenetic regulation of cell state transitions and the therapeutic implications in breast cancer [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 3833.
Abstract 3838: HDAC5-mediated deacetylation promotes SATB1 oncogenic functions
Authors: Sharma Shalakha , Das Dr. Sanjeev 
Published: September 2020

Abstract
HDAC5, a class IIa histone deacetylase is a prominent transcriptional regulator. The functions of HDAC5 have been shown to be regulated via phosphorylation-dependent nuclear-cytoplasmic shuttling. Phosphorylation of two conserved Ser259 and Ser498 residues by calcium/calmodulin dependent protein kinase promotes HDAC5 nuclear export. Dysregulation of HDAC5 has been implicated in development of many pathogenic conditions including cardiac hypertrophy and cancer. However, the mechanisms underlying the role of HDAC5 in tumorigenesis are not well understood. In order to explore the role of HDAC5 in tumorigenesis, we performed a proteomic screen and identified several interacting proteins of HDAC5. In vitro and in vivo studies further confirmed SATB1 as a novel interacting partner of HDAC5. SATB1 (Special AT rich binding protein 1) is a global genome organizer that recruits chromatin remodeling proteins to epigenetically regulate several genes. It has been recently reported to be overexpressed in various cancers and associated with malignant behavior of cancer cells. Our studies revealed SATB1 as a novel substrate of HDAC5-mediated deacetylation during early phase of genotoxic stress. We also mapped the site of deacetylation to the highly conserved K411 residue of SATB1. Upon prolonged genotoxic stress when HDAC5 undergoes nuclear export, SATB1 acetylation was observed. Thus, we screened a shRNA library targeting nuclear histone acetyltransferases and identified Tip60 as the cognate histone acetyltransferase involved in SATB1 acetylation at K411 residue. Next we performed qPCR array and found SATB1 upregulates the expression of genes involved in tumor suppression in acetylation-dependent manner. Increased SATB1 acetylation leads to decreased cell proliferation capacity, migration and invasiveness of tumor cells. Furthermore, studies in mouse tumor models confirmed that HDAC5 promotes SATB1-mediated tumorigenesis. Taken together, our findings add to the substrate repertoire of HDAC5 and provides key insights into SATB1-mediated tumorigenesis.
Citation Format: Shalakha Sharma, Dr. Sanjeev Das. HDAC5-mediated deacetylation promotes SATB1 oncogenic functions [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 3838.
Abstract 3840: KLF5 acetylation promotes bone metastatic growth of prostate cancer by activating CXCR4/IL-11 and subsequent osteoclast differentiation
Authors: Zhang Baotong , Li Yixiang , Wu Qiao , Xie Lin , Barwick Benjamin , Dong Jin-Tang 
Published: September 2020

Abstract
Advanced prostate cancer most commonly spreads to bones. Although denosumab or zoledronic acid is recommended for prostate cancer patients with bone metastases to prevent or delay skeletal-related events, no significant benefits in terms of cancer-specific and overall survival have been observed. Some chemotherapies are available for the treatment of bone metastasis, but eventually all such tumors develop resistance. Additionally, the underlying mechanisms of prostate cancer bone metastasis and its resistance to chemotherapy are still poorly understood. In this study, we report that TGF-β-induced acetylation of the basic transcription factor Krüppel-like factor 5 (KLF5) frequently occurred in prostate cancer cells located in both the mouse and human bone microenvironments. Using multiple in vitro and in vivo systems, we demonstrated that tumor cells expressing acetylated KLF5 (Ac-KLF5) enhanced prostate cancer-induced bone lesions by promoting osteoclast differentiation. As revealed by RNA-Seq and ChIP-Seq analyses, Ac-KLF5 transcriptionally activated CXCR4 expression, the silence of which attenuated Ac-KLF5-enhanced osteoclast differentiation. A further screening on the paracrine signaling indicates that IL-11 mediated the promoting effect of the Ac-KLF5/CXCR4 axis on osteoclast differentiation. These findings indicate that the TGF-β/Ac-KLF5/CXCR4/IL-11 signaling axis from bone to tumor and then to bone again is a crucial pathway responsible for TGF-β mediated vicious cycle in bone metastasis. More importantly, targeting CXCR4 using FDA approved drugs AMD3100 selectively sensitizes Ac-KLF5-expressing tumors and bone metastases to docetaxel treatment. These findings provide a rationale for targeting Ac-KLF5/CXCR4 signaling as a novel therapeutic strategy in advanced prostate cancer patients with bone metastases.
Citation Format: Baotong Zhang, Yixiang Li, Qiao Wu, Lin Xie, Benjamin Barwick, Jin-Tang Dong. KLF5 acetylation promotes bone metastatic growth of prostate cancer by activating CXCR4/IL-11 and subsequent osteoclast differentiation [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 3840.
Abstract 388: Antigen-loaded Fe3O4 nanoparticles for the stimulation and tracking of dendritic cell based vaccine
Authors: Qi Yafei , Du Yang , Tian Jie , Jin Zhengyu , Li Yuan 
Published: September 2020

Abstract
Background and purpose:Dendritic cells (DCs), as the antigen-presenting cells, play important roles in immunotherapy. The antigen uptake, cross-presentation, maturation and lymph node migration of DCs are crucial steps for immune system activation. Herein, we aim to construct a novel Fe3O4@SIINFEKL-TAT nanoparticle, which mainly consists of Fe3O4 nanosphere core and transmembrane peptide TAT on the shell, and also with the model antigen SIINFEKL peptide, a peptide of the ovalbumin (OVA) antigen. To explore the feasibility of Fe3O4@OVA-TAT to stimulate the maturation of DCs and the in vivo tracking of DCs using MRI-MPI dual-modal imaging.
Methods: On the one hand, TAT peptide facilitates the uptake of the Fe3O4@OVA-TAT nanoparticles into DCs, and subsequently the OVA antigens are cross-presented to stimulate DCs maturation. On the other hand, Fe3O4 nanosphere core can function for both magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) dual-modality imaging, which can realize the in vivo dynamic tracking of DCs migration to lymph nodes.
Results: The laser confocal microscope experiments confirmed that Fe3O4@OVA-TAT can be taken up through the early endosome-late endosome pathway, but the fluorescent signal of the imaging probe is located outside the lysosome after 4 h, which suggested that Fe3O4@OVA-TAT could escape lysosomal uptake and cross-present. The CD80 and CD86 flow cytometry results showed that Fe3O4@OVA-TAT, LPS, and OVA can stimulate 90%, 60%, and 40% of BMDCs to mature, respectively (p &lt; 0.05). After the Fe3O4@SIINFEKL-TAT labeled DCs was injected into the mouse footpad, the MRI T2WI signal decreased and the MPI signal increased in the popliteal and inguinal lymph nodes 24 h post-injection, suggesting that our DC vaccine can efficiently migrate to the lymph node.
Conclusions: Our study showed that Fe3O4@SIINFEKL-TAT nanoparticles can stimulate and trace DCs in in vivo, which pave the way for further development and precision application of DC vaccine in both preclinical and clinical settings.
Citation Format: Yafei Qi, Yang Du, Jie Tian, Zhengyu Jin, Yuan Li. Antigen-loaded Fe3O4 nanoparticles for the stimulation and tracking of dendritic cell based vaccine [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 388.
Abstract 3905: Human liver organoids for disease modeling of fibrolamellar hepatocellular carcinoma
Authors: Croteau Nicole J. , Requena David , Lalazar Gadi , Ng Denise , Levin Solomon , Shebl Bassem , Wang Ruisi , Hammond William J. , Saltsman James A. , Gehart Helmuth , Clevers Hans , LaQuaglia Michael P. , Simon Sanford 
Published: September 2020

Abstract
Fibrolamellar Hepatocellular Carcinoma (FLC) is a usually lethal liver cancer affecting adolescents and young adults without previous liver disease. FLC is characterized by a ~400kb nucleotide deletion resulting in a fusion of a heatshock protein cofactor, DNAJB1, with the catalytic subunit of protein kinase A (PRKACA). One limitation to the study of this disease is the lack of in vitro models. Organoids have shown utility as a model system for studying many diseases, including cancer. This study describes the development and characterization of FLC tumor organoids. With IRB approval, normal liver and FLC tumor tissue was obtained from patients undergoing surgical resection. Liver cells were isolated from the tissue samples and placed into a 3D basement membrane matrix and the media supplemented with growth factors specific to promote liver organoid expansion. Normal and tumor organoids were analyzed by microscopy for morphology, by PCR for presence of the DNAJB1-PRKACA chimeric transcript, by Western blot for chimeric protein expression, and by RNA sequencing for transcriptomic changes. Eight organoid lines have been developed from normal liver and eight from FLC tumor tissue, including multiple independent organoids developed from different metastases from the same patient. A distinct morphological difference between normal liver organoids and FLC tumor organoids can be seen with either brightfield microscopy or with H&E. The DNAJB1-PRKACA chimeric transcript was detected in all of the tumor tissue and tumor organoids by RT-PCR and not detected in any of the normal tissue or organoids. The presence of the DNAJB1-PRKACA fusion protein was verified by Western blot in tumor organoids and tissue but not detectable in the normal tissue. The RNA sequencing analysis shows clustering of tumor organoids with tumor tissue. Tumor organoids injected subcutaneously in mice grew as tumors. Now that the normal and tumor organoids have been developed and validated, they are being used for screening for potential therapeutics.
Citation Format: Nicole J. Croteau, David Requena, Gadi Lalazar, Denise Ng, Solomon Levin, Bassem Shebl, Ruisi Wang, William J. Hammond, James A. Saltsman, Helmuth Gehart, Hans Clevers, Michael P. LaQuaglia, Sanford Simon. Human liver organoids for disease modeling of fibrolamellar hepatocellular carcinoma [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 3905.
Abstract 3907: Invasive properties of GSCs with known IDH1 status into human cerebral organoids
Authors: Munyeshyaka Maxime , Singh Sanjay , Gumin Joy , Yang Jing , Ledbetter Daniel , Lang Frederick 
Published: September 2020

Abstract
Glioblastomas (GBM) are malignant Grade IV tumors whose prognosis for patients remains dismal, with median survival of 14.6 months after the standard therapy. GBMs have a high proliferative index and are highly invasive to normal brain tissue. GBMs characteristically exhibit areas of necrosis and recruitment of abnormal blood vessels. The most common form of GBMs are primary GBMs (~95%), with no prior clinical history and have poor clinical outcome. Secondary GBMs arise from lower-grade gliomas and are associated with IDH1 mutation (R132H/C/G/S). Methylation profiling identified a subtype of GBMs called glioma-CpG island methylator phenotype (G-CIMP+ve) GBMs, and this subtype yields significant survival benefit compared to non-G-CIMP+ve GBMs and is mostly associated with IDH1 mutant GBMs. GBM biology is traditionally investigated by utilizing patient-derived tumor cells (e.g GBM stem-like cells “GSCs”) in vitro and in vivo as orthotopic xenografts in immunocompromised mouse models. However, these systems lack normal human neural tissue, and therefore the contribution of the normal human neural microenvironment is unable to be studied using these systems. This shortcoming can be addressed by utilizing human cerebral organoids (COs). Cerebral organoids are derived from induced pluripotent stem cells and can serve as in vitro model systems to recapitulate the human brain microenvironment where multiple neural cell types are represented. A recent study showed that GSCs invade and proliferate in human cerebral organoids, and these tumors phenocopy parental tumors. Here, we hypothesized that the invasiveness of GSCs within COs is dictated by IDH1 status, where IDH1 wild-type are more aggressive than IDH1 mutant GSCs. To test our hypothesis, we utilized 45 day-old COs and three GSCs lines (2 IDH1 wild-type and 1 IDH1 mutant) for in vitro invasion and proliferation assays. These GSCs stably express either green or red fluorescent proteins and can be used as surrogates to identify GSCs within COs. Upon co-incubation for various time points, these GSC bearing COs were fixed, embedded, sectioned, and imaged with a confocal microscope. Our preliminary results show that GSCs with wild-type IDH1 appear to be more aggressive within COs. With further research studies, the use of COs will elucidate the contribution of the normal brain microenvironment to the growth and invasiveness of GBMs.
Citation Format: Maxime Munyeshyaka, Sanjay Singh, Joy Gumin, Jing Yang, Daniel Ledbetter, Frederick Lang. Invasive properties of GSCs with known IDH1 status into human cerebral organoids [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 3907.
Abstract 3954: Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma
Authors: Roshini Arivazhagan , Goparaju Chandra , Nandhu Mohan S. , Longo Sharon L. , Longo John A. , Chou Joan , Middleton Frank A. , Pass Harvey I. , Viapiano Mariano S. 
Published: September 2020

Abstract
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor of the pleura with poor prognosis and limited therapeutic options. Fibulin-3 (gene EFEMP1) is an extracellular matrix protein found in the parenchyma and pleural effusions of MPM, which has been proposed as prognostic biomarker complementing diagnostic biomarkers -such as mesothelin- for this cancer type. However, the functions and potential mechanisms of fibulin-3 in MPM remain completely unknown. To further define the relevance of fibulin-3 in MPM we performed gain- and loss-of-function experiments by respectively overexpressing fibulin-3 in normal mesothelial cells or knocking down its expression in MPM cells, followed by evaluation of cell viability, colony formation, invasion and chemoresistance. We also evaluated changes in gene expression and signaling mechanisms after fibulin-3 downregulation. Furthermore, a novel anti-fibulin-3 antibody was developed and tested for its ability to recognize fibulin-3 in mesothelioma, inhibit pro-tumoral signaling, and disrupt tumor growth in orthotopic MPM models. Fibulin-3 downregulation decreased viability, clonogenic capacity, and invasiveness of MPM cell lines, whereas overexpression of this protein increased the same phenotypic traits in normal mesothelial cells. At the molecular level, fibulin-3 regulated the activation of PI3K/Akt and NFkB signaling and correlated with a gene expression signature required for cell adhesion and motility, matching its cellular effects. Loco-regional delivery of anti-fibulin-3 had a marked cytostatic effect and significantly increased median survival and the number of long-term surviving animals with stable disease. Our work reveals that fibulin-3 is a relevant therapeutic target in mesothelioma, adding to its relevance as prognostic biomarker and encouraging further development of anti-fibulin-3 targeted therapies for this cancer type.
Citation Format: Arivazhagan Roshini, Chandra Goparaju, Mohan S. Nandhu, Sharon L. Longo, John A. Longo, Joan Chou, Frank A. Middleton, Harvey I. Pass, Mariano S. Viapiano. Validation of the extracellular matrix protein fibulin-3 as a molecular target in malignant pleural mesothelioma [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 3954.