bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4232: Spatially constrained tumor growth affects the patterns of clonal selection and neutral drift in cancer genomic data
Authors: Chkhaidze Kate , Heide Timon , Werner Benjamin , Williams Marc J. , Huang Weini , Caravagna Giulio , Baker Ann-Marie , Graham Trevor A. , Sottoriva Andrea 
Published: August 2019

Abstract
Quantification of the effect of spatial tumor sampling on the patterns of mutations detected in next-generation sequencing data is largely lacking. Here we use a spatial stochastic cellular automaton model of tumor growth that accounts for somatic mutations, selection, drift and spatial constrains, to simulate multi-region sequencing data derived from spatial sampling of a neoplasm. We show that the spatial structure of a solid cancer has a major impact on the detection of clonal selection and genetic drift from bulk sequencing data and single-cell sequencing data. Our results indicate that spatial constrains can introduce significant sampling biases when performing multi- region bulk sampling and that such bias becomes a major confounding factor for the measurement of the evolutionary dynamics of human tumors. We present a statistical inference framework that takes into account the spatial effects of a growing tumor and allows inferring the evolutionary dynamics from patient genomic data. Our analysis shows that measuring cancer evolution using next-generation sequencing while accounting for the numerous confounding factors requires a mechanistic model-based approach that captures the sources of noise in the data.
Citation Format: Kate Chkhaidze, Timon Heide, Benjamin Werner, Marc J. Williams, Weini Huang, Giulio Caravagna, Ann-Marie Baker, Trevor A. Graham, Andrea Sottoriva. Spatially constrained tumor growth affects the patterns of clonal selection and neutral drift in cancer genomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4232.
Abstract 4235: Phosphorylation of Serine 861 in the ECT2 guanine nucleotide exchange factor activates Rho family GTPases and is a biomarker for several tumor types
Authors: Wang Dunrui , Qian Xiaolan , Eng Sarah , Nellore Shivani , Papageorge Alex G. , Lowy Douglas R. 
Published: August 2019

Abstract
The Rho family of GTPases, which cycle between inactive GDP-bound and active GTP-bound states, have high activity in many cancers. One mechanism for their activation is by guanine nucleotide exchange factors (GEFs), which stimulate the replacement of GDP-bound Rho with GTP-bound Rho. In this study, we report phosphorylation of Epithelial Cell Transforming 2 (ECT2), which is a Rho family-specific GEF, is a biomarker in several tumor types, based on bioinformatic analysis and biological assays. Our analysis of the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) database found that Serine 861 (S861) in ECT2 is more highly phosphorylated in several tumor types compared to its phosphorylation in the relevant normal tissue. S861 phosphorylation is 2.1-fold and 2.4-fold higher in colon cancer and ovarian cancer, respectively, and high S861 phosphorylation in breast cancer is correlated with a poorer prognosis. Phosphorylation of S861 is especially high in triple-negative breast cancer, as it is 2.3-fold higher in this type compared with the other types of breast cancer. Increased phosphorylation of S861 is associated increased ECT2 mRNA and protein levels in colon cancer and breast cancer. In experimental studies, siRNA knockdown of endogenous ECT2 in two triple-negative breast cancer lines resulted in lower levels of RhoA-GTP, Rac-GTP, and Cdc42-GTP, and led to reduced cell migration, cell proliferation, and anchorage-independent growth, suggesting that ECT2 is a key regulator of cellular signaling and oncogenic growth in the triple-negative lines. Conversely, ectopic expression of wild-type ECT2 induced increased levels of RhoA-GTP, Rac-GTP, and Cdc42-GTP and promoted migration, proliferation, and anchorage-independent growth. Compared with wild type ECT2, ectopic expression of ECT2 carrying a phospho-defective (S861A) or phospho-mimic (S861D) mutation, respectively, reduced or enhanced ECT2 GEF and biological activities. Our results indicate that phosphorylation of S861 enhances the pro-oncogenic activity of ECT2, which is correlated with the increased phosphorylation of S861 in the three cancer types, the increased expression of ECT2 in two of these cancer types, and the prognostic significance of S861 phosphorylation in breast cancer. * Dunrui Wang and Xiaolan Qian are Equal contributors
Citation Format: Dunrui Wang, Xiaolan Qian, Sarah Eng, Shivani Nellore, Alex G. Papageorge, Douglas R. Lowy. Phosphorylation of Serine 861 in the ECT2 guanine nucleotide exchange factor activates Rho family GTPases and is a biomarker for several tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4235.
Abstract 424: Genomic instability changes of circulating tumor DNA reflect the responses to chemotherapy or targeted therapy in advanced gastric cancer
Authors: Chen Zuhua , Zhang Cheng , Li Beifang , Niu Yunyun , Chen Limeng , Zhang Mengqi , Yang Jing , Lu Sijia , Gao Jing , Shen Lin 
Published: August 2019

Abstract
Background: Gastric cancer was characterized by frequent somatic copy number alterations and high genomic instability, yet the significance of genomic instability and its changes implicated by drug treatment in advanced gastric cancer (AGC) remain unclear. In this study, we investigated genomic instability changes of circulating tumor DNA (ctDNA).
Methods: A total of 101 plasmas and paired blood cells from 26 patients with AGC before (N=26) and after (N=75) treatment were prospectively collected. Plasma ctDNA was separated and assessed for copy number variations (CNV) by whole genome sequencing (WGS), and we assessed the correlation between genomic indexes and therapeutic response.
Results: Genomic instability with diverse patterns was observed in 20 of 26 patients (77%) prior to drug treatment. For patients with high (N=20) level genomic instability prior to drug treatment, the response rate (55%, 11/20) was significantly higher than that (17%, 1/6) in patients with low level (N=6) genomic instability (P=0.17). Notably, genomic instability changed with the administration of drugs, which reflected its correlation with therapeutic response. All ctDNAs (94%, 14/15) collected at the time of partial response (PR) after treatment displayed low-genomic instability. However, 52% ctDNAs (13/25) collected at the time of progressive disease (PD) after treatment showed high-level genomic instability. Furthermore, several patterns of CNV were categorized in ctDNAs. CNV pattern after acquiring drug resistance were largely unchanged with respect to CNV baseline patterns.
Conclusions: Genomic instability based on ctDNA can be used to predict and monitor therapeutic response in gastric cancer, although validation in larger cohort would be necessary.
Citation Format: Zuhua Chen, Cheng Zhang, Beifang Li, Yunyun Niu, Limeng Chen, Mengqi Zhang, Jing Yang, Sijia Lu, Jing Gao, Lin Shen. Genomic instability changes of circulating tumor DNA reflect the responses to chemotherapy or targeted therapy in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 424.
Abstract 4261: Upregulation of miR-34b, miR-892a and inhibition of p-glycoprotein play an important role for melatonin-induced apoptosis and autophagy in vincristine-resistant human oral cancer cells
Authors: Yang Shun-Fa , Hsieh Ming-Ju , Lin Chiao-Wen 
Published: August 2019

Abstract
Multidrug-resistance was resistance of cells to a variety of drugs normally used in tumor treatment. The related mechanism of drug resistance in oral cancer has not been completely explained. Melatonin is an endogenously-produced molecule involved in active biological mechanisms including antiproliferation, oncogene expression modulation, antitumor invasion and migration, and anti-inflammatory, antioxidant, and antiangiogenic effects. Despite these numerous actions, the effect of melatonin on vincristine (VCR)-resistant human oral cancer cells still largely unknown. Present study analyzed the role of melatonin on VCR-resistant human oral cancer cells along with the underlying mechanism. We determined that melatonin induces apoptosis and autophagy of VCR-resistant oral cancer cell; these actions are mediated by AKT, p38, and JNK. Melatonin inhibits ABCB1 and ABCB4 expression in vitro/vivo. Melatonin decrease drug resistance and promotes VCR-resistant oral cancer cell execute apoptosis through upregulation of miR-892a and miR-34b-5p expression. The expression of miR-892a and miR-34b-5p are related with melatonin-induced apoptosis, but not autophagy. Thus, melatonin is a potential novel agent in chemotherapy for VCR-resistant human oral cancer cell lines.
Citation Format: Shun-Fa Yang, Ming-Ju Hsieh, Chiao-Wen Lin. Upregulation of miR-34b, miR-892a and inhibition of p-glycoprotein play an important role for melatonin-induced apoptosis and autophagy in vincristine-resistant human oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4261.
Abstract 4263: Autophagic ovarian cancer cells exhibit substantially enhanced sensitivity to ALK inhibition
Authors: Blessing Alicia M. , Mao Weiqun , Pang Lan , Rask Philip , Lu Zhen , Bast Robert C. 
Published: August 2019

Abstract
One of the major factors contributing to poor outcomes for patients with ovarian cancer is the persistence of dormant, drug resistant cancer cells after primary surgery and chemotherapy. The persistent cancer found in positive second look operations is poorly vascularized and autophagy is widespread in more than 80% of cases. Consequently, drugs that regulate survival in autophagic cancer cells may be much more active when administered as maintenance therapy than when used to treat gross recurrent disease. Using unbiased siRNA screens, we have identified target genes that regulate the survival of ovarian cancer cells that are undergoing autophagy-induced by the re-expression of DIRAS3 (ARHI) or by serum starvation. Knockdown of the anaplastic lymphoma kinase (ALK) significantly reduced survival of ovarian cancer cells that were undergoing autophagy. Importantly, FDA-approved ALK inhibitors, including crizotinib, exhibited significantly greater toxicity after induction of autophagy by upregulation of DIRAS3 or serum starvation in 5 ovarian cancer cell lines. Induction of autophagy by upregulation of DIRAS3 or serum starvation in ovarian cancer cells reduced the IC50 of crizotinib and other ALK inhibitors ranging from 1.5 to 20-fold (all p-values &lt;0.05). Crizotinib treatment in autophagic cancer cells enhanced autophagy and apoptosis via a decrease in p-STAT3 and BCL-2 signaling. Selective targeting of p-STAT3 or BCL-2 also resulted in significantly greater toxicity after induction of autophagy by upregulation of DIRAS3 or serum starvation in multiple ovarian cancer cells. Inducible upregulation of DIRAS3 by doxycycline in the first 6 weeks prompted autophagy and dormancy in two separate xenograft models (SKOV3 and OVCAR8). Crizotinib treatment of dormant autophagic SKOV3 xenografts prolonged median survival by 9.7 weeks (p&lt;0.0032) and cured a subset of mice. Thirteen of fifteen mice (87%) bearing SKOV3 xenografts and nine of eleven mice (82%) bearing OVCAR8 xenografts, were tumor free at 200 days compared to the other three control arms (overall survival, p&lt;0.0001 and p&lt;0.05, respectively). Our studies suggest that ALK inhibitors might provide an effective agent to eliminate autophagic, dormant, drug resistant ovarian cancer cells that remain after conventional cytoreductive surgery and combination chemotherapy.
Citation Format: Alicia M. Blessing, Weiqun Mao, Lan Pang, Philip Rask, Zhen Lu, Robert C. Bast. Autophagic ovarian cancer cells exhibit substantially enhanced sensitivity to ALK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4263.
Abstract 427: Detection and molecular characterization of circulating tumor cells in advanced head and neck squamous cell carcinoma
Authors: Tada Hiroe , Takahashi Hideyuki , Ishii Hiroki , Kuwabara-Yokobori Yuki , Shino Masato , Chikamatsu Kazuaki 
Published: August 2019

Abstract
Malignant properties of tumor cells are genetically and epigenetically altered during tumor development and progression. Moreover, tumor cells rapidly change to treatment resistant phenotype by various therapeutic pressures, and not only become more heterogeneous but also possess metastatic potential. Detection and characterization of circulating tumor cells (CTCs) in the bloodstream of cancer patients have been currently remarked as a valuable tool for real-time evaluation of tumor tissue with phenotypic heterogeneity in the diagnosis and treatment of various cancers, however these have been still challenging. In the present study, we investigated the presence of CTCs and their molecular characterization by the combination of microfiltration system and RT-qPCR method. Peripheral blood samples were collected from 30 patients with advanced head and neck squamous cell carcinoma (HNSCC) and passed through two CellSieveTM microfilters using a low-pressure filtration system. The existence of CTCs collected from the first filter was determined by the expression of epithelial-related genes (KRT19, EPCAM, EGFR, or MET), then the expression of cell proliferation (PIK3CA and CCND1)-, EMT (SNAI1 and VIM)-, cancer stemness (CD44, NANOG, and ALDH1A1)-, and immune regulation (CD47, CD274, and PDCD1LG2)-related genes was analyzed for molecular characterization of CTCs. The gene expression in cells collected from the second filter was used for normalization of target genes. Sixteen (53.3%) of 30 patients were positive for at least one epithelial-related gene. Interestingly, the number of patients with locoregional recurrence or distant metastasis in 16 CTC-positive patients was 7 (43.8%) or 5 (31.3%); whereas that in 14 CTC-negative patients was 2 (14.3%) or 1 (7.1%), respectively. The gene expression profile in CTCs collected from 16 CTC-positive patients has revealed remarkable heterogeneity between HNSCC patients. Of 16 CTC-positive patients, PIK3CA was overexpressed in 56.3%, CCND1 in 43.8%, SNAI1 in 62.5%, VIM in 43.8%, CD44, in 50.0%, NANOG in 31.3%, ALDH1A1 in 56.3%, CD47 in 62.5%, CD274 in 37.5%, and PDCD1LG2 in 31.3%. Our results suggest that CTCs may play an important role in locoregional recurrence as well as distant metastasis in HNSCC. Further molecular profiling at the single-cell level of CTCs is needed to clarify the clinical significance of molecular phenotype of CTCs.
Citation Format: Hiroe Tada, Hideyuki Takahashi, Hiroki Ishii, Yuki Kuwabara-Yokobori, Masato Shino, Kazuaki Chikamatsu. Detection and molecular characterization of circulating tumor cells in advanced head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 427.
Abstract 4274: RNA methylation regulates osteosarcoma growth and progression via autophagy
Authors: Subbarayalu Panneerdoss , Yadav Pooja , Rao Manjeet 
Published: August 2019

Abstract
Osteosarcoma (OS) is the most common primary bone tumor and third most common cancer in children/teens, after lymphomas and brain tumors. OS is treated by surgery and multi-modal chemotherapy. Even though this treatment regimen has improved the 5-year survival rate to 60-70%, once osteosarcoma metastasize to lung and other bones, the survival is significantly reduced. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with the chemotherapy. Since several decades, there hasn’t been any improvement in the osteosarcoma treatment outcome. Therefore, it is important to understand the molecular mechanism of osteosarcoma growth and metastasis and an urgent need to develop effective drug, which can be safe and effective for treating OS patients. We discovered that RNA methylation may regulate OS growth and progression by affecting autophagy. Our studies revealed that RNA demethylase AlkB homolog 5 (ALKBH5) supports OS viability, migration and invasion as well as tumor growth. We discovered several autophagy related genes were significantly altered in ALKBH5-silenced OS cells compared to scrambled control. Importantly, levels of LC3, which is a universal marker for monitoring autophagy, was significantly increased in ALKBH5 depleted OS cells. Furthermore, we found that autophagy initiation complex protein ULK1 level was drastically increased in ALKBH5-silenced cells when compared to scrambled control. To further establish the role of autophagy in osteosarcomogenesis, we treated OS cells with chloroquine, which is a well-known autophagy inhibitor and is currently being investigated for treating adult cancers in clinical trials. Interestingly, silencing of ALKBH5 significantly improved the efficacy of chloroquine as revealed by drastically reduced viability and invasive ability of OS cells. In conclusion, our study is first to shows that RNA methylation plays a critical role osteosarcoma growth and progression by regulating autophagy.
Citation Format: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao. RNA methylation regulates osteosarcoma growth and progression via autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4274.
Abstract 4279: Heterogeneous LC3A expression regulates lung cancer cell plasticity
Authors: Miao Chia-Cheng , Hwang Wen , Chou Yu-Ting 
Published: August 2019

Abstract
Tumor metastasis is considered as the main cause that contributes to high mortality during lung cancer progression. Autophagy is a self-cleaning process to maintain cell integrity of intracellular organelles and proteins. To date, the role of autophagy in lung tumor metastasis remains elusive. Here, we report that lung tumors display a heterogeneous expression pattern of the autophagy mediator LC3A, the high expression of which is associated with low metastasis risk. We found a group of lung cancer cells contain differential LC3A expression levels and exhibit plasticity characterized by distinct proliferative and invasive properties. Immunofluorescence staining and immunoblotting assays revealed that LC3A-mediated autophagy is more active in highly proliferative but minimally invasive lung cancer cells than their lowly proliferative but highly invasive counterpart. Clonogenic analysis and cell cycle assays showed that LC3A silencing attenuated cellular growth, causing G1/S cell cycle arrest in highly proliferative lung cancer cells. Highly proliferative lung cancer cells exhibited a higher oxygen consumption rate, accompanied with an elevated oxygen species (ROS) level, compared to their lowly proliferative counterpart. Pharmacological inhibition of autophagy with chloroquine promoted the ROS production in highly proliferative lung cancer cells but not in the highly invasive counterpart. SOX2 expression enhanced LC3A expression and promoted proliferation but inhibited invasiveness in lung cancer cells. Knockdown of LC3A expression in SOX2-high proliferative cells enriched SOX2-low cells, exhibiting decreased proliferation but increased invasiveness. Combined, our findings provide substantial evidence to suggest that LC3A cooperates with SOX2 signaling to regulate lung cancer cell plasticity.
Citation Format: Chia-Cheng Miao, Wen Hwang, Yu-Ting Chou. Heterogeneous LC3A expression regulates lung cancer cell plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4279.
Abstract 4281: LT-IIc, a bacterial type II heat-labile enterotoxin, induces specific lethality in triple negative breast cancer cells by modulaton of autophagy and induction of apoptosis and necroptosis
Authors: Masso-Welch Patricia A. , Berlingeri Sofia Girald , King-Lyons Natalie D. , Mandell Lorrie , Hu John C. , Greene Christopher , Federowicz Matthew , Cao Peter , Heakal Yasser 
Published: August 2019

Abstract
Despite the recent advances in breast cancer treatment, triple negative breast cancer (TNBC) remains a serious health problem with limited treatment options. Poor prognosis is due to the development of chemoresistance. To discover novel therapeutic approaches to treat TNBC, we screened cholera toxin (CT) and the members of the bacterial type II heat-labile enterotoxin family (LT-IIa, LT-IIb, and LT-IIc) for their capacity to induce cell death in TNBC cells. LT-IIc, but not the other toxins, significantly reduced viability of the TNBC cell lines BT549 and MDA-MB-231 (IC50 = 82.32 nM). LT-IIc had no significant cytotoxic effects on MCF10A (IC50 = 2600 nM), a non-tumorigenic breast epithelial cell line, and minimal effects on MCF7 and T47D, ER+ breast cancer cells, or SKBR-3, HER2+ cells. LT-IIc stimulated autophagy through inhibition of the mTOR pathway, while simultaneously inhibiting autophagic progression, as observed by the accumulation of LC3B-II and p62 proteins. Morphologically, LT-IIc induced accumulation of enlarged LAMP2+ autolysosomes selectively in TNBC cells. Bafilomycin A1, an inhibitor of autophagic flux, blocked the formation and/or retention of these autolysosomes. The increase in caspase 3, 7 activity and annexin V staining indicated that LT-IIc induced an apoptotic response. Co-treatment with necrostatin-1, however, demonstrated that the lethal response to LT-IIc is elicited, at least in part, by concomitant induction of necroptosis. Collectively, these experiments demonstrate that LT-IIc acts bifunctionally, inducing autophagy while simultaneously blocking autolysosomal progression in TNBC cells, resulting in specific cytotoxicity in this breast cancer subtype.
Citation Format: Patricia A. Masso-Welch, Sofia Girald Berlingeri, Natalie D. King-Lyons, Lorrie Mandell, John C. Hu, Christopher Greene, Matthew Federowicz, Peter Cao, Yasser Heakal. LT-IIc, a bacterial type II heat-labile enterotoxin, induces specific lethality in triple negative breast cancer cells by modulaton of autophagy and induction of apoptosis and necroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4281.