bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4503: Role of ER-associated degradation in rhabdomyosarcoma
Authors: Sannino Sara , Guerriero Christopher J. , Brodsky Jeffrey L. 
Published: July 2017

Abstract
Due to their higher proliferation rate, most cancers experience impaired ATP generation, hypoxia, hypoglycemia, and increased genetic mutations that may perturb cellular and protein homeostasis. Persistent stress conditions induce the unfolded protein response (UPR) as well as increased expression of molecular chaperones, such as Hsp70, to modulate cell fate. Our recent studies demonstrate how perturbing cytosolic Hsp70 activity with a small molecule modulator, MAL3-101, induces rhabdomyosarcoma cell (RMS13) death, patient-derived cells of one of the most common soft-tissue cancers in children. MAL3-101 addition activates PERK- and CHOP-dependent RMS13 cell death in a dose dependent manner (Sabnis et al., PNAS, 2016). To identify the mechanism that links UPR-triggered cell death and cytosolic Hsp70 inhibition, an isogenic MAL3-101-resistant cell line was generated (MAR4C). Even though both RMS13 and MAR4C cells were equally sensitive to a diverse panel of therapeutic compounds, we now find that they have different efficiencies of ER-associated degradation (ERAD), a quality control pathway that degrades misfolded proteins in the secretory pathway and that lessens proteotioxic stress. Specifically, MAR4C cells remove both soluble and membrane associated ERAD substrates faster than RMS13 cells and possess increased levels of ubiquitinated proteins upon proteasomal inhibition. These data suggest that higher ERAD efficiency is required for MAR4C cell survival upon Hsp70 inhibition and highlight an unexpected link between cytosolic Hsp70 inhibition and the ERAD pathway in cancer cells. Moreover, RNAseq analysis suggests that select redox-related ER quality control chaperones are differentially expressed between MAR4C and RMS13 cells, and lower levels of the BiP and PDI chaperones and Peroxiredoxin 4 are found in MAR4C cells. Because new therapeutic agents as well as reliable biomarkers are critically needed in rhabdomyosarcoma and other cancers, this study sheds light on one mechanism of cancer pathogenesis and suggests that different cancer subtypes modulate ER quality protein quality uniquely.
Citation Format: Sara Sannino, Christopher J. Guerriero, Jeffrey L. Brodsky. Role of ER-associated degradation in rhabdomyosarcoma [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 4503. doi:10.1158/1538-7445.AM2017-4503
Abstract 4508: Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression
Authors: Ranjan Alok , Ramachandran Sharavan , Gupta Nehal , Srivastava Sanjay 
Published: July 2017

Abstract
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Experimental and clinical evidences suggested that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapies. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo. (Ranjan and Srivastava, Scientific Reports: 2016;6:26165; PMID: 27189859), however the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum (ER) stress could lead to autophagy and inhibit tumor progression. In the current study, we demonstrated that penfluridol induced ER stress in BxPC-3, AsPC-1 and Panc-1, pancreatic cancer cell lines as indicated by up regulation of ER stress markers such as BIP, CHOP and IRE1α after treatment with penfluridol in a concentration-dependent manner. Inhibiting ER stress by pre-treatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOPsiRNA, blocked penfluridol-induced autophagy. These results clearly indicated that penfluridol induced ER stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP and IRE1α expression in the tumors lysates from penfluridol treated mice as compared to tumors from control mice. Altogether, our study established that penfluridol induced ER stress mediated autophagy in pancreatic tumor. Our study opened a new therapeutic target for advanced chemotherapies against pancreatic cancer. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH).
Citation Format: Alok Ranjan, Sharavan Ramachandran, Nehal Gupta, Sanjay Srivastava. Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression [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 4508. doi:10.1158/1538-7445.AM2017-4508
Abstract 4512: The landscape of hypoxia-driven alternative splicing in breast cancer
Authors: Choudhry Hani , Oikonomopoulos Spyridon , Yu Peng , Ivan Cristina , Ivan Mircea , Harris Adrian L. , Ragoussis Jiannis 
Published: July 2017

Abstract
Tumor hypoxia is generally associated with poor patient outcome and resistance to therapy. Hypoxia has an impact on multiple pathways inside the cell and a widespread effect on phenotype. Here we determined the changes in transcript architecture that arise as result of alternative splicing in hypoxic cells. A panel of breast cancer cell lines that include the Luminal A and B, HER2+, Triple-Negative subcategories grown in hypoxic and normoxic conditions were subjected for deep RNA-sequencing. Depending on the cell lines we found between 23- 927 splicing events with 3-45% of them also present in the differentially expressed fraction of genes. This points to an extensive isoform switching control independently of the transcriptional control of the genes themselves. The splicing events appear on genes responsible for mRNA processing (splicing, nuclear export and catabolism) as well as initiation of translation. Members of the SR family of proteins involved in RNA splicing, appear to be potential regulators of the biogenesis of the hypoxia specific splicing events. The differentially spliced exons are frequently part of both the coding and noncoding isoforms of a given gene potentially indicating a switch between these two types under hypoxia. Ten of the hypoxia specific splicing events were also found to be associated with the hypoxia status of primary breast cancer samples taken from The Cancer Genome Atlas (TCGA) database. Altogether, these data demonstrate the important role of hypoxia in driving alternative splicing events in breast cancer.
Citation Format: Hani Choudhry, Spyridon Oikonomopoulos, Peng Yu, Cristina Ivan, Mircea Ivan, Adrian L. Harris, Jiannis Ragoussis. The landscape of hypoxia-driven alternative splicing in breast cancer [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 4512. doi:10.1158/1538-7445.AM2017-4512
Abstract 4527: Estimating tumor cell dissemination rates through lymph and blood via computational modeling
Authors: Barrette Anne Marie , Lenoir Benedicte , Skobe Mihaela , Birtwistle Marc R. 
Published: July 2017

Abstract
Metastasis is the primary cause of death from most cancer types, but the relative rates of tumor cell migration through lymphatic versus blood routes remains an open question. Here we combine data from a xenograft model of metastatic breast cancer with a computational model of tumor cell growth and dissemination to help answer this question. Orthotopic mouse xenografts using the triple negative breast cancer cell line MDA-MB-231 allowed for monitoring of metastatic cells within the primary tumor, bloodstream, lymph nodes, and lungs. Experiments resembling a pulse-chase method helped inform and parameterize the model to the rate of dissemination to the lymph nodes and lungs. Our ordinary differential equation model describes primary tumor growth as the balance between proliferation and death, with the proliferative fraction decreasing with tumor size, and the apoptotic or necrotic fraction increasing with tumor size. Intravasation to both lymph and blood rapidly increases early in tumor growth, followed by a decay to a low rate of tumor cell release well before the primary tumor grows to its saturating size. The mouse data guided our parameter estimations based on the assumptions that disseminated tumor cell death rate is greatest in the harsh environment of the blood and lowest in the more accommodating lymph node, and that metastatic cells seeding in the lymph nodes and lungs follow similar growth dynamics as the primary tumor only with far fewer total cells. We are currently performing sensitivity analysis to explore the range of relative rates of tumor cell dissemination that fit the in vivo data, and thus gain insight into tumor cell dynamics within the different compartments. These analyses will allow us to estimate what the relative contributions of blood versus lymphatic tumor cell dissemination are to overall metastatic burden, as well as suggest experiments that further constrain these estimates. Such combined experimental and modeling analysis lend insight into where one might detect pre-metastatic cells early in disease progression or suggest new targets for anti-metastasis drugs based on the dominant mode of dissemination.
Citation Format: Anne Marie Barrette, Benedicte Lenoir, Mihaela Skobe, Marc R. Birtwistle. Estimating tumor cell dissemination rates through lymph and blood via computational modeling [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 4527. doi:10.1158/1538-7445.AM2017-4527
Abstract 4532: Adrenal metastases in lung cancer: Clinical implications of a mathematical model
Authors: Mason Jeremy M. , Ciccarella AnneMarie , Marx-Rubiner Lori , Bazhenova Lyudmila , Newton Paul K. , Bethel Kelly , Nieva Jorge J. , Kuhn Peter 
Published: July 2017

Abstract
Adrenal gland metastases are common in lung cancer. It is well recognized that aggressive treatment of solitary adrenal metastases leads to improved outcomes but the exact nature of adrenal deposits is not well understood. Controversy exists as to the routing of cancer cells to the adrenal gland with some believing that this transmission is lymphatic, in contrast to the more generally accepted theory of hematogenous spread. Using an autopsy dataset of 3827 untreated cancer patients, we use the metastatic distribution of common primary cancer types to create Markov models of progression. The anatomical sites of spread in the body represent states in the model, while the transition probability between states represents the probability of metastatic spread from one site to another. We then use the Markov models to run Monte Carlo simulations of random walkers representing circulating tumor cells traveling within the body to simulate metastatic spread. We calculate mean first passage times (MFPT) to each site as a representative of time to metastasis formation. Analysis of 6 common cancer types (bladder [n=120 autopsies; 289 metastases], breast [n=432; 2235], colorectal [n=161; 420], lung [n=560; 859], ovarian [n=418; 806], and prostate [n=62; 212]) from the dataset showed distinct metastatic distributions across the populations. MFPT calculations to anatomical sites in the 6 analyzed primary cancer types indicated model progression times to the adrenal gland similar to the regional and distal lymph nodes in only lung cancer. The times associated with adrenal gland in the other primary cancers were similar to other metastatic sites of hematogenous spread. The Markov models created strongly support the lymphatic theory for metastatic spread to the adrenal glands. After performing a literature review to look for the biological plausibility of the simulated results, we believe evidence supports this theory and validates the models. This could explain improved survival for patients in whom solitary adrenal metastases are managed aggressively with surgical or radiation modalities. In order to further validate this theory, we are calling for clinical trials prospectively testing this hypothesis.
Citation Format: Jeremy M. Mason, AnneMarie Ciccarella, Lori Marx-Rubiner, Lyudmila Bazhenova, Paul K. Newton, Kelly Bethel, Jorge J. Nieva, Peter Kuhn. Adrenal metastases in lung cancer: Clinical implications of a mathematical model [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 4532. doi:10.1158/1538-7445.AM2017-4532
Abstract 4535: Tumor cell division rate heterogeneity explains in vitro clonal dominance
Authors: Palm Margriet M. , Elemans Marjet , Beltman Joost B. 
Published: July 2017

Abstract
The cells that make up a tumor exhibit large phenotypic and genotypic variation, which strongly influences the effectiveness of cancer therapy. A typical manifestation of intratumor heterogeneity is the presence of a few clones that represent most of the tumor population, i.e. clonal dominance. Such heterogeneity could potentially be caused by the occurrence of different ratios of cancer stem cells and differentiated cells per clone, or, alternatively, clonal dominance may be caused by heterogeneity of division rates between clones. Previously published work, applying lineage tracing with genetic barcodes to in vitro iterated growth and passage experiments demonstrated that clonal dominance was accompanied by clone loss and partial overlap in dominant clones between biological replicates [1]. To identify the source of these observations, we build a computational model that simulates the iterated growth and passage experiments. By varying the 'division rules' in the model, we can quantitatively predict the evolution of the clone distribution for the aforementioned hypotheses. In this manner, we show that clonal dominance does not appear in simulations where all cells divide at a uniform rate, even when the population is subdivided in cancer stem cells and differentiated cells. However, when the division rates vary between clones and are inherited from parent cells, dominant clones appear. These simulations also closely match the in vitro evolution of clone loss and clonal overlap between biological replicates. Altogether, our findings suggest that tumor cells exhibit a heritable variability in the division rates of individual cells.
References
[1] Porter, S. et al. (2014). Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo. Genome Biology, 15(5), R75.
Citation Format: Margriet M. Palm, Marjet Elemans, Joost B. Beltman. Tumor cell division rate heterogeneity explains in vitro clonal dominance [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 4535. doi:10.1158/1538-7445.AM2017-4535
Abstract 4556: MEDI5395: An armed oncolytic Newcastle disease virus
Authors: Carroll Danielle , Harper James , Jon Travers , Burke Shannon , Franks Ruth , Navarro Christel , Cheng Xing , Wilkinson Robert , Jin Hong 
Published: July 2017

Abstract
Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell lysis occurs as a natural consequence of the viral life cycle and released virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of releasing multiple tumour antigens that may further induce an immune-mediated therapeutic response. Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of preclinical cancer models and in PhI clinical studies as an oncolytic agent, oncolysate or whole cell vaccine. Using reverse genetics, we have generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. Furthermore we have enhanced the immune modulatory properties of NDV by engineering the virus to express granulocyte/macrophage colony-stimulating factor (GM-CSF). We have evaluated the biological characteristics of recNDVGM-CSF (MEDI5395) in vivo and in vitro. MEDI5395 selectively replicates in and kills a wide variety of human and mouse tumour cell lines. Additionally infection of cancer cells with MEDI5395 results in the increased production and secretion of pro-inflammatory cytokines and chemokines which are able to recruit mediators of both the innate and adaptive immune responses. MEDI5395 is a potent activator of the type I interferon response. In vivo, using a range of syngeneic and xenograft models we have demonstrated that NDV treatment has robust anti-tumour activity. In a HT1080 fibrosarcoma xenograft model a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. In syngeneic mouse tumour models, which support minimal viral replication MEDI5395 treatment causes significant changes in the local immune suppressive microenvironment and results in long-lasting anti-tumour immune responses. These responses are further enhanced in models that permit greater replication and also when combined with immune checkpoint blockade. The inherent properties of NDV (self-propagation, tumour-selective replication, and immunostimulatory properties) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients.
Citation Format: Danielle Carroll, James Harper, Travers Jon, Shannon Burke, Ruth Franks, Christel Navarro, Xing Cheng, Robert Wilkinson, Hong Jin. MEDI5395: An armed oncolytic Newcastle disease virus [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 4556. doi:10.1158/1538-7445.AM2017-4556
Abstract 456: Functional analysis of DEC1 and DEC2 in cancer metabolism
Authors: Sato Fuyuki , Muragaki Yasueru 
Published: July 2017

Abstract
Basic helix-loop-helix (bHLH) transcription factor DEC1 (bHLHE40/Stra13/Sharp2) and DEC2 (bHLHE41/Sharp1) are clock genes that show a circadian rhythm in various tissues. However, the function of DEC1 and DEC2 in metabolism has not been poorly understood. AMP-activated protein kinase (AMPK) activity plays important roles in the metabolic process and circadian rhythm. However, how circadian rhythm of phosphorylation of AMPK (pAMPK) is regulated has been yet understood. The aim of this study is to investigate whether there is a direct correlation between DEC1 and DEC2 expression and AMPK activity in normal and cancer cells. There was an inverse relationship between DEC1 expression and AMPK activity. DEC1 protein and pAMPK showed a circadian rhythm in the mouse liver with different peak levels. Knocking down DEC1 expression increased pAMPK, whereas overexpression of DEC1 decreased it. DEC1 bound to the E-box of the LKB1 promoter, decreased LKB1 activity and total protein levels. In addition, pAMPK immunoreactivity was strongly detected in the liver and lung of DEC2 knockout mice compared with that of wild-type mice. Interestingly, medium change induced the circadian rhythm of DEC2, but not DEC1 in cancer cells. We conclude that DEC1 and DEC2 negatively regulates AMPK activity via LKB1, and play important roles in cancer cell metabolism.
Citation Format: Fuyuki Sato, Yasueru Muragaki. Functional analysis of DEC1 and DEC2 in cancer metabolism [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 456. doi:10.1158/1538-7445.AM2017-456
Abstract 4570: Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression
Authors: Aoki Kazunori , Shibasaki Chihiro , Hashimoto Hisayoshi , Narumi Kenta , Kudo Chie 
Published: July 2017

Abstract
Type I interferon (IFN) is a pleiotropic cytokine regulating the cancer cell death and immune response. IFN-α can effectively induce an antitumor immunity by the activation of tumor-specific T cells and maturation of dendritic cells in various animal models. It is widely known that an induction of tolerance by the tumor is one of the critical mechanisms involved in tumor progression and resistance for immune therapy. Extensive studies have shown that CD4+Foxp3+ regulatory T cells (Tregs) are critical in controlling antitumor immune responses in the tumor microenvironment. Since the effect of type I IFN on an immunotolerant microenvironment is unknown, we investigated the immunological effects of intratumoral IFN-α gene transfer on tumor-infiltrating Tregs in a mouse model.
Here, to examine whether the expression of IFN-α affects the immunotolerant microenvironment in tumors, CT26 murine colon cancer tumors were directly injected once with 1 x 108 PFU of IFN-α-expressing adenovirus (Ad-mIFN). The injection of Ad-mIFN significantly suppressed the tumor growth. We found that intratumoral IFN-α gene transfer significantly decreased the frequency of Tregs per CD4+ T cells in tumors compared with control vector injection.
We hypothesized that Treg-homing cytokines such as CCL17 and CCL22 cytokines are involved in the reduction of tumor-infiltrating Tregs by the Ad-mIFN injection. The IFN-α expression significantly suppressed of CCL17 and CCL22 expression of tumors, and the expression of CCR4 and CCR5 expression on Tregs was not changed. IFN-α protein significantly suppressed CCL17 of CT26 cells in vitro in a dose-dependent manner. Then, we constructed CCL17 shRNA-transduced CT26 cells (CT26shCCL17) to examine the immunological role of CCL17 in vivo. The frequency of Tregs per CD4+ T cells was significantly reduced in subcutaneous tumors of CT26shCCL17 cells (25.9 %), and tumor growth was inhibited compared with that of control shRNA-transduced CT26 cells (39.4%), suggesting CCL17 has an important role to migrate Tregs into tumors. The study demonstrated that IFN-α gene delivery creates an environment strongly supporting the enhancement of antitumor immunity through the suppression of Tregs.
Citation Format: Kazunori Aoki, Chihiro Shibasaki, Hisayoshi Hashimoto, Kenta Narumi, Chie Kudo. Intratumoral IFN-α gene transfer reduces trafficking of Tregs into tumor by inhibition of CCL17 expression [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 4570. doi:10.1158/1538-7445.AM2017-4570