bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1327: Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg
Authors: Okamoto Takako , Chen Song , Yeo Syn , Guan Jun-Lin 
Published: August 2018

Abstract
Autophagy genes have been reported to have either tumor promoting or inhibition functions in various cancers, but it is convoluting because of autophagy-independent functions of the respective autophagy genes. We previously reported that suppression of Fip200, an essential autophagy gene, inhibited tumor growth of PyMT driven mammary tumors. To dissect the specific autophagy-dependent function of FIP200 in these tumors, we recently established Fip200 Knock-in PyMT tumor mice with MMTV-Cre (cKI), allowing for conditional inhibition of autophagy in PyMT driven tumors without perturbing the non-autophagy functions of FIP200 . Compared to wild type (WT) tumors, tumor initiation, growth and metastasis were significantly suppressed in both cKI tumors and conditional Fip200 deleted tumors (cKO). Microarray analysis (GSEA) showed that adipogenesis related genes were significantly enriched in WT tumors compared to cKO tumors. The mRNA expression and protein expression of Pparg, one of the master regulators of adipogenesis, were significantly increased with autophagy induction under starvation condition (especially Glucose starvation) in PyMT isogenic cells compared to Fip200 KO and KI cells. Many Pparg target genes were down-regulated in autophagy deficient tumors. Among these, CD36, a free fatty acid (FFA) transporter, was also decreased compared to WT tumors. This suggests that FFA may have important roles as an energy source for PyMT tumor cells to survive under starvation conditions. In conclusion, our results indicate that tumor promotion of PyMT driven tumors was dependent on canonical autophagy. Our future studies will address the detailed mechanism of autophagy dependent tumor growth through metabolic regulation by Pparg.
Citation Format: Takako Okamoto, Song Chen, Syn Yeo, Jun-Lin Guan. Autophagy facilitates tumor promotion in PyMT tumors through up-regulation of Pparg [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 1327.
Abstract 1333: Inactivation of NBR1 enhances sensitivity to rapamycin on human urothelial cancer cell lines through AMPK/ULK1-mediated autophagy
Authors: Kim Myeong Joo , Cho Min Ji , Chang In Ho , Whang Young Mi 
Published: August 2018

Abstract
Rapamycin has been highly evaluated in clinical therapeutic intervention for cancer patients as a specific inhibitor of the mammalian target of rapamycin (mTOR) kinase. Rapamycin also stimulates autophagy and mitophagy to remove damaged cells as a regulator of general autophagy. Previously, we identified increased expression of mRNA levels of NBR1 (autophagy cargo receptor) by inhibiting mTOR signaling in human urothelial cancer cell lines. Therefore, we investigated whether loss of NBR1 sensitizes human urothelial cancer cells to autophagic stimulation and stress-induced mitochondrial insults by treatment with rapamycin. NBR1-deficient cells exhibited enhanced sensitivity to rapamycin that was associated with increased autophagy and mitochondrial defects. Loss of NBR1 expression altered the cellular response to rapamycin treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Moreover, rapamycin treatment also induced autophagy activity through AMPK activation in NBR1-deficient cells, which was involved in blocked mTOR signaling and activated unc-51 like autophagy activating kinase 1 (ULK1). NBR1-deficient cells exhibited profound mitochondrial dysfunction in response to rapamycin treatment as evidenced by Δψm collapse, ATP depletion, ROS accumulation and apoptosis activation. Therefore, our findings provide a rationale for rapamycin treatment of NBR1-deficient human urothelial cancer through induction of autophagy activity by regulating the AMPK/mTOR signaling pathway, indicating that NBR1 can be a potential candidate for the treatment of human urothelial cancer. (NRF-2015R1A1A1A0500110 to I.H.C., NRF-2016R1D1A1B03933826 to Y.M.W., and the Korea Health Technology R&D Project HI17C0710 to C.I.H.)
Citation Format: Myeong Joo Kim, Min Ji Cho, In Ho Chang, Young Mi Whang. Inactivation of NBR1 enhances sensitivity to rapamycin on human urothelial cancer cell lines through AMPK/ULK1-mediated autophagy [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 1333.
Abstract 1347: Autophagy inhibitor, chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1 in pancreatic cancer
Authors: Lee Seonmin , Kim Kyu-Pyo , Yoo Changhoon , Kim Danbi , Kim Chorong , Chae Heejung , Kang Jihoon , Ryoo Baek-Yeol 
Published: August 2018

Abstract
Autophagy is a regulated, destructive catabolic mechanism to degrade cellular organelles and macromolecules. In cancer, the role of autophagy in tumor cell survival or death is still controversial because of each tumor type has a heterogeneity on metabolic status and microenvironment. In this study, we showed that autophagy inhibitor, chloroquine (CQ), increased sensitivity to oxaliplatin in pancreatic cancer cell lines. The autophagy inhibitor, chloroquine effectively inhibited autophagic flux which is important for maintenance of pancreatic cancer cell metabolism and drug resistance. Treatment of oxaliplatin after blockade of autophagy increased chromatin instability and facilitated loss of nuclear HMGB1. In consequence the cells turned into apoptotic cell death. The drug combination effect of chloroquine and oxaliplatin shows that inhibition of autophagy by chloroquine carry on dual role in pancreatic cancer cell death. First, chloroquine occurs cytosolic redox imbalance based on increase mitochondrial ROS (mtROS) following rupture of autolysosome. Second, the cytosolic redox imbalance occurred by chloroquine induces failure of autophagy by incapacitation of cytosolic HMGB1. Here we suggest that autophagy inhibition by chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1. Also we suggest HMGB1 as a new target for therapeutic agents against pancreatic cancer.
Citation Format: Seonmin Lee, Kyu-Pyo Kim, Changhoon Yoo, Danbi Kim, Chorong Kim, Heejung Chae, Jihoon Kang, Baek-Yeol Ryoo. Autophagy inhibitor, chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1 in pancreatic 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 1347.
Abstract 1355: Mutation signatures including APOBEC in cancer cell lines
Authors: Harris Reuben S. 
Published: August 2018

Abstract
Background: Multiple endogenous and exogenous sources of DNA damage contribute to the overall mutation burden in cancer, with distinct and overlapping combinations contributing to each cancer type. Many mutation sources result in diagnostic mutation signatures, which can be deduced from tumor genomic DNA sequences. Examples include spontaneous hydrolytic deamination of methyl-cytosine bases in CG motifs (AGEING signature) and C-to-T and C-to-G mutations in 5'-TC(A/T) motifs (APOBEC signature).
Methods: The deconstructSigs R package was used to analyze single base substitution mutation signatures in over 1000 cancer cell lines. Two additional approaches were used to analyze the APOBEC mutation signature.
Results: Most cell lines show evidence for multiple mutation signatures. For instance, the AGEING signature, which is the largest source of mutation in most primary tumors, predominates in the majority of cancer cell lines. The APOBEC mutation signature is enriched in cancer cell lines from breast, lung, head/neck,
bladder, and cervical cancers, where this signature also comprises a large fraction of all mutations.
Conclusions: The single base substitution mutation signatures of cancer cell lines often reflect those of the original tumors from which they are derived. Cancer cell lines with enrichments for distinct mutation signatures such as APOBEC have the potential to become model systems for fundamental research on the underlying mechanisms and for advancing clinical strategies to target these processes and, ultimately, constrain tumor evolvability.
Citation Format: Reuben S. Harris. Mutation signatures including APOBEC in cancer cell lines [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 1355.
Abstract 136: T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens
Authors: Machado Jose C. , Reis Joana , Fernandes Margarida , Silva Rafaela , Cirnes Luis , Carneiro Fatima , Costa Jose L. 
Published: August 2018

Abstract
A cornerstone of the biological process which mediates response to immunotherapy in cancer patients is the expression of neoantigens resulting from somatic mutations in cancer cells. Little attention has been paid so far to the neoantigen's immune cell counterpart, the T-cell receptor (TCR). In this study, we aimed at characterizing the tumor infiltrating T-cell repertoire in colorectal cancer (CRC), and to evaluate evidence for neoantigen driven T-cell expansion within the tumor microenvironment. To characterize the T-cell repertoire, we used the Ion AmpliSeq Immune Repertoire Assay Plus with an Ion S5 XL system. This assay works with as little as 10ng of starting total RNA, allows 400bp read length, and offers complete characterization of the CDR1, CDR2 and CDR3 regions. A cohort of 20 CRC cases was used, including microsatellite instability (MSI) positive and MSI-negative cases. Our results show a higher T-cell richness in distal CRC samples compared with proximal samples (p=0.04), and lower T-cell richness in M1 as compared with M0 cases (p=0.0001). No association was observed with MSI status, inflammatory infiltrate, tumor grade or lymph node metastasis. We observed that the T-cell repertoire in CRC samples is highly convergent compared to the peripheral blood lymphocyte repertoire of healthy donors (p&lt;0.0001). In CRC samples we observed evidence of selection of TCR clonotypes coding for the same CDR3 aminoacid sequence, suggesting neoantigen-driven TCR convergence. TCR clone overlap was observed only between pairs of samples (4 pairs of primary tumor and metastasis samples available) from the same patient, and not between samples from different patients, suggesting high tumor specificity of T-cell clonotype selection. A validation cohort of CRC cases, including additional pairs of primary tumor and metastasis samples, is currently being analyzed to validate our findings. In this study we provide evidence of T-cell clonotype selection in CRC driven by tumor-specific neoantigens. The specificity of this process is further reinforced by the T-cell clonotype overlap within patients. It remains to be seen whether it is possible to map convergent T-cell clonotypes to its respective tumor neoantigens.
Citation Format: Jose C. Machado, Joana Reis, Margarida Fernandes, Rafaela Silva, Luis Cirnes, Fatima Carneiro, Jose L. Costa. T-cell clonotype convergence in colorectal cancer driven by tumor-specific neoantigens [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 136.
Abstract 1361: Micro RNA-200C is one of the important Fanconi Anemia (FA) pathway downstream regulators in lung cancer
Authors: Duan Wenrui , Tang Shirley , Gao Li , Dotts Kathleen , Fink Andrew , Kalvala Arjun , Aguila Brittany , Villalona-Calero Miguel A. 
Published: August 2018

Abstract
The Fanconi Anemia (FA) pathway is essential for human cells to maintain integrity following DNA damage. This pathway is involved in the endogenous repair of double stranded DNA breaks and homologous recombination as well as repair of DNA cross-linking caused by exogenous agents. Cancers with defective FA pathway are expected to be more sensitive to cross-link based therapy, or to treatments in which additional repair mechanisms are targeted. We have recently reported the detection of 22% of NSCLC to be FA functionally inactive by Fanconi Anemia Triple Staining Immunofluorescence (FATSI) test. Studies have shown involvement of certain micro RNA (miRNA) as regulatory elements in the development of lung cancer. We set out to evaluate potential involvement of miRNAs in the regulation of the Fanconi Anemia (FA) pathway. Using Nanostring counter miRNA array we screened 734 different miRNA expression in two FA defective lung cancer cells and matched control cells along with two FA pathway deficient lung tumors and matched non-tumor lung tissue samples. Selected miRNA expression were validated with real-time PCR analysis. miRNA target gene expression was analyzed through AmpliSeq RNA gene expression analysis. Among 734 different miRNAs, a cluster of microRNAs were found to be up-regulated including an important cancer related micro RNA, miR-200C. Nanostring data showed that miR-200C was increased 7.5 fold on average in the FA defective lung cancer cells as compared to control cell. An average of 22 fold increase in miR-200C was detected in the FA defective lung tumor tissues comparing to matching non-tumor tissues. AmpliSeq analysis showed the ZEB1(zinc finger E-box binding homeobox 1) mRNA expression was down regulated in10 out 10 lung tumors (100%) comparing to non-tumor tissues, and 9 out of 10 samples (90%) showed reduction in ZEB2 expression. MiRNA-200C has been reported as a negative regulator of epithelial-mesenchymal transition (EMT) and inhibiting cell migration and invasion by promoting the upregulation of E-cadherin through targeting ZEB1 and ZEB2 transcription factors. Our findings indicate that the FA pathway regulates downstream genes through regulation of miRNAs in lung cancer. MiR-200C appears to be one of the most important FA downstream regulators in lung cancer. Validation with a larger sample size will be needed to confirm our findings.
Citation Format: Wenrui Duan, Shirley Tang, Li Gao, Kathleen Dotts, Andrew Fink, Arjun Kalvala, Brittany Aguila, Miguel A. Villalona-Calero. Micro RNA-200C is one of the important Fanconi Anemia (FA) pathway downstream regulators in lung 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 1361.
Abstract 137: Pharmacologic activation of integrin CD11b as a novel therapeutic strategy against lung cancer
Authors: Geraghty Terese , Rajagopalan Anugraha , Khan Samia , Varner Judith , Gupta Vineet 
Published: August 2018

Abstract
Lung cancer is the leading cause of cancer related deaths in the United States. With a 5-year survival rate of 18%, lung cancer patients are in immediate need of new therapeutic options. A major problem facing immunotherapy for cancer is the active immune suppression by the tumor. Tumors show presence of large numbers of tumor associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization to the tumor, and promote tumor survival. Integrin CD11b is highly expressed on TAMs and is essential for their recruitment and biological functions. Reasoning that CD11b activity is important for controlling tumor growth, we developed a novel small molecule agonist called leuhadherin-1 (LA1), which activates CD11b. We found that CD11b activation by LA1 significantly reduced tumor growth in wild type mice bearing Lewis Lung Carcinoma (LLC) tumors as early as one week post treatment. Conversely, LLC tumors grew at a faster rate in CD11b-/- mice, compared to wild type mice, showing that CD11b is important for controlling tumor growth. Importantly, LA1 treatment in tumor bearing CD11b-/- mice did not show any efficacy, demonstrating the specificity of LA1 to CD11b. These data suggest that CD11b activation via LA1 modulates TAMs in tumors and is a novel therapeutic strategy against cancer.
Citation Format: Terese Geraghty, Anugraha Rajagopalan, Samia Khan, Judith Varner, Vineet Gupta. Pharmacologic activation of integrin CD11b as a novel therapeutic strategy against lung 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 137.
Abstract 1374: Modeling the CRISPR/Cas9 structural complex with sgRNA and DNA
Authors: Wary Anita 
Published: August 2018

Abstract
The ability of genome editing tool to correct genetic disease, or edit the tumor causing gene, will not only benefit human race, but also plants and animal kingdom. The CRISPR/Cas9 system can be used to target specific genomic loci by single guide RNAs (sgRNAs). Using publicly available literature, we have modeled the structure of Streptococcus pyogenes Cas9 molecule in complex with sgRNA and its target DNA at 2.5 A° resolution. The crystal structure determination revealed a two-lobed architecture made of: (a) target recognition and (b) nuclease lobes, positioning the sgRNA:DNA hetero-duplex in a positively charged groove at their interface. While the recognition lobe interacts with the sgRNA and DNA, the nuclease lobe contains the HNH and RuvC nuclease domains that are responsible for cleavage of the complementary and non-complementary target DNA strands, respectively. The nuclease lobe also harbors a carboxyl-terminal domain to provide additional specificity for interaction with the protospacer adjacent motif (PAM) DNA sequence. This structural analyses show the molecular mechanism of RNA-guided DNA targeting by Cas9, thus providing the CRIPSR/Cas9 genetic machinery its ability to edit specific DNA sequence. (Key Ref: Nishimasu H et al., Cell. 2014;156:935-49)
Citation Format: Anita Wary. Modeling the CRISPR/Cas9 structural complex with sgRNA and DNA [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 1374.
Abstract 1384: The epigenetic modifier EZH2 represses antitumor immunity in melanoma
Authors: Tiffen Jessamy , Shklovskaya Elena , Gallagher Stuart , Gunatilake Dilini , Hersey Peter 
Published: August 2018

Abstract
Despite major advances in immuno- and targeted therapies for metastatic melanoma, not all patients respond to such treatments and the development of therapy resistance remains a key obstacle. Novel targets are required and the epigenetic modifier EZH2 may represent such a solution. EZH2 methylates histones causing chromatin compaction and silencing of gene expression. Aberrant EZH2 in cancer results in the silencing of hundreds of tumor-suppressor genes that would normally constrain cancer growth, and 26% of patients in the Australian Melanoma Genome Project (AMGP) display such abnormal EZH2. Using ChIP-seq and microarrays to reveal downstream EZH2 target genes, we identified many tumor-suppressor genes including some that play a role in the antitumor immune response. Interestingly, xenografts in immune-deficient NOD SCID mice showed no significant inhibition in tumor growth when treated with an EZH2 inhibitor. However, growth inhibition was achieved when the same experiment was performed in nude mice, which retain some mediators of innate immunity. The effect of EZH2 overexpression in melanoma on immune-mediated rejection was studied in an inducible in vivo model. Subcutaneous B16 tumors expressing model antigen were initially rejected but relapsed in the majority of immunodeficient mice transferred with CD4 T cells. Long-term (120-day) survival was reduced from 40% to 22% if the tumors also overexpressed EZH2. Our studies suggest that aberrant EZH2 in melanoma drives aggressive disease via suppression of genes that would normally trigger the antitumor immune response. The progression of several preclinical, small-molecule inhibitors of EZH2 remains promising.
Citation Format: Jessamy Tiffen, Elena Shklovskaya, Stuart Gallagher, Dilini Gunatilake, Peter Hersey. The epigenetic modifier EZH2 represses antitumor immunity in melanoma [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 1384.
Abstract 14: Preclinical evaluation of novel HIF-1α/P300 binding inhibitors
Authors: Strope Jonathan D. , Harris Emily M. , Beedie Shaunna L. , Chau Cindy H. , Cook Kristina M. , Schofield Christopher J. , Gustafson Kirk R. , Figg William D. 
Published: August 2018

Abstract
A key component of tumor progression and metastasis is the hypoxic response. The hypoxic response regulates angiogenesis, tumor invasion, and metabolism. The Hypoxia Inducible Factor (HIF) is the transcriptional system responsible for the hypoxic response. The inhibition of the hypoxic response via inhibition of the HIF-1 pathway by disrupting its association with the transcriptional coactivator p300 presents a potential therapeutic target for multiple cancers where HIF is upregulated. To that end, we describe the preclinical development of previously described novel marine pyrroloiminoquinone alkaloids found using a HIF-1α/p300 assay in a high throughput screen of extracts from the National Cancer Institute's Natural Products Repository. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein−protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription. The 2 lead candidates, discorhabdin L and H were assessed in inhibition of angiogenesis in an in vitro HUVEC assay and ex vivo rat aortic ring assay. The compounds were also evaluated for in vivo efficacy in prostate cancer cell tumor xenografts. Results show that development of these compounds for clinical use is warranted and may prevent the progression of multiple tumor types.
Citation Format: Jonathan D. Strope, Emily M. Harris, Shaunna L. Beedie, Cindy H. Chau, Kristina M. Cook, Christopher J. Schofield, Kirk R. Gustafson, William D. Figg. Preclinical evaluation of novel HIF-1α/P300 binding inhibitors [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 14.