bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A03: A brain cancer cell migration simulator based on a motor-clutch model
Authors: Bangasser Benjamin L. , Rosenfeld Steven R. , Odde David J.
Published: May 2016

WHO Grade IV astrocytoma, also known as glioblastoma, is an invasive disease where cell migration drives dispersion of tumor cells throughout the brain. To predict cell migration speeds in complex mechanochemical environments, we developed a cell migration simulator based on our published motor-clutch framework [1-3]. One of the key predictions of our previous modeling is that cell traction force is biphasic with respect to environmental stiffness, i.e. there is an optimal stiffness at which cell traction force is maximal. To test whether such optimality exists within a whole cell migration simulator, we extended our model to allow for multiple cellular protrusions in 1D, 2D, or 3D environments. The cell migration simulator imposes that forces balance and that masses of key elements- actin, adhesions, and myosin motors- are conserved. Using the Gillespie stochastic simulation algorithm implemented in matlab, we simulated cell traction force, F-actin retrograde flow, cell aspect ratio, and cell migration as a function of cell stiffness. We found that all four variables depends biphasically on simulated environmental stiffness with approximately overlapping optima. In addition, the model predicts that the optimal stiffness can be shifted by coordinate shifting of motor and adhesive clutch numbers, a prediction that we are now testing experimentally in vitro. Overall, our modeling results predict that effective anti-migratory treatment of patients will require knowledge of the cell migration speed landscape within parameter space. In particular, we predict that simultaneously inhibiting motors and clutches will be beneficial for patients whose tumors operate near the optimum, largely ineffective for those below the optimum, and potentially detrimental to those above the optimum. Thus, our cell migration simulator provides dynamic physical biomarkers that can potentially be used to classify glioblastoma patients for more precise treatment.

References:

1. Bangasser, B.L. and D.J. Odde, Master Equation-Based Analysis of a Motor-Clutch Model for Cell Traction Force. Cellular and Molecular Bioengineering, 2013. 6: p. 449-459.

2. Bangasser, B.L., S.S. Rosenfeld, and D.J. Odde, Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. Biophys J, 2013. 105(3): p. 581-92.

3. Chan, C.E. and D.J. Odde, Traction dynamics of filopodia on compliant substrates. Science, 2008. 322(5908): p. 1687-91.

Citation Format: Benjamin L. Bangasser, Steven R. Rosenfeld, David J. Odde. A brain cancer cell migration simulator based on a motor-clutch model. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A03.
Abstract A09: Effects of Podocalyxin on neural stem/progenitor cells
Authors: San Isabelle V. Leefa Chong , Prost Gaelle , Nuber Ulrike
Published: May 2016

Podocalyxin (PODXL) is a highly glycosylated and sialylated protein found mainly on podocytes and up-regulated in various types of tumors. Known to be a marker of hematopoietic progenitors and pluripotent stem cells, PODXL is also increasingly considered a marker of malignancy in several aggressive tumor types. Though the exact role of PODXL in tumors is not yet established, it has increasingly been shown in vitro to be involved in cell migration and invasion.

We found Podxl to be highly expressed in murine tumorigenic neural stem/progenitor cells. To investigate effects of elevated Podxl levels in neural stem/progenitor cells (NSPs), Podxl or an empty control construct were over-expressed in these cells. Podxl-overexpressing NSPs did not form brain tumors upon intracranial transplantations, indicating that high levels of this gene alone are not sufficient for tumorigenesis. In vitro studies however revealed how Podxl might contribute to the development and /or maintenance of tumors. Podxl overexpression had a positive effect on cell number, sphere formation and cell viability.

To find out how Podxl exerts its pro-survival effects, the proteome of Podxl-overexpressing and empty control NSPs was analysed by mass spectrometry. These experiments revealed an up-regulation of Annexin A2, a calcium-regulated phospholipid binding protein interacting with the cytoskeleton and extracellular matrix. In addition to elevated Annexin A2 protein levels, we also found increased transcript levels indicating that PODXL stimulates expression of the Annexin A2 gene. NSPs lacking Annexin A2 and overexpressing Podxl are less viable than wild type Podxl-overexpressing NSPs, suggesting that PODXL-mediated pro-survival effects can at least in part be explained by increased Annexin A2 levels. We are now investigating how Podxl and Annexin A2 mechanistically interact to enhance cell viability

Citation Format: Isabelle V. Leefa Chong San, Gaelle Prost, Ulrike Nuber. Effects of Podocalyxin on neural stem/progenitor cells. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A09.
Abstract A12: Genomically unstable glioblastoma are sensitive to Parp inhibition
Authors: McDonald Kerrie L. , Khasraw Mustafa , Jue Toni Rose , Joshi Swapna , Yin Julia
Published: May 2016

Background: The development of effective targeted drugs for the treatment of glioblastoma (GBM) represents a major unmet need. Veliparib (ABT-888; Abbvie) inhibits both PARP1 and PARP2 (poly[ADP-ribose] polymerase). The successful clinical application of veliparib and other PARP inhibitors (PARPi) will be assisted by the identification of predictive biomarkers.

Materials and Methods: We performed whole genome sequencing (WGS) on ten GBM specimens with matched normal DNA. Mutations were detected using qSNP and GATK and indels called with Pindel and GATK. Somatic structural variants were identified using the qSV package. For all ten specimens we developed patient derived cell lines (PDCLs). We tested the efficacy of the combination of veliparib and temozolomide (TMZ) on all of the PDCLs.

Results: Strikingly, in 2 patient samples denoted as G89 and G54, the mutation rate was at least 16-fold higher compared to the other 8 participants. G89 and G54 exhibited a large number of single nucleotide variants (SNVs), insertions, deletions and structural variant (SV) events (>2 million) when compared to the other 8 patient samples. The scale of genomic instability suggested defects in DNA maintenance, which could potentially define sensitivity to DNA damaging agents. Upon closer examination of the mutational profile of G89 and G54, mutations were found in at least one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. We also detected mutations in other genes involved in DNA maintenance such as XRCC4, FANCA, FANCD2, ATR, RPA1, REV3L and PARP1. We designated these patients' GBM as U-GBM class. We found the U-GBM class of tumors, G89 and G54 to be hypersensitive to the combination of TMZ/veliparib.

Conclusion: Mutations in DNA maintenance pathways may be a method for selecting patients for therapies involving the combination of DNA damaging agents such as radiotherapy, and PARP inhibitors. Additionally, the signature associated with genomically unstable GBM may be a method of identifying potential responders to PARP inhibitor therapy.

Citation Format: Kerrie L. McDonald, Mustafa Khasraw, Toni Rose Jue, Swapna Joshi, Julia Yin. Genomically unstable glioblastoma are sensitive to Parp inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A12.
Abstract A31: Cyclic NGR peptide functionalized PEG-PLGA nanoparticles as dual-targeting carrier for site specific antitumor drug delivery
Authors: Gupta Dr. Madhu , Sharma Dr. Vikas , Agrawal Prof. G.P. , Vyas Prof. S.P.
Published: May 2016

CD13 receptors are abundantly overexpressed in tumor cells as well as in neovasculature. The polymeric nanoparticles (NPs) as the nanomodules for anticancer drug carriers are well known. Nowadays, targeted delivery options are becoming a fascinating approach, so CD13 receptors was selected as a targeted site and NPs as a delivery system. By combining all the issue, a cyclic NGR (cNGR) peptide as a ligand was coupled on the terminal end of polyethylene glycol-b-poly(lactic-co-glycolic acid) (PEG-b-PLGA) and prepared the dual targeted polymeric NPs (cNGR-PEG-PTX-NPs) in order to enhance the intracellular delivery of anticancer drug to the tumor cells and tumor endothelial cells via ligand-receptor interaction. In-vitro cytotoxicity studies confirmed that the presence of cNGR enhanced the cytotoxic efficiency by 2.8 folds in human umbilical vein endothelial (HUVEC) cells, while cytotoxicity was improved by 2.6 folds in human fibrosarcoma (HT-1080) cells as compared to non-specific stealth NPs. Compared with other tested NPs, cNGR-PEG-PTX-NPs revealed more cytotoxicity by inducing more apoptosis, higher cell uptake and more G2/M phase arrest. The tumor volume inhibition rate was 59.7% in case of cNGR-PEG-PTX-NPs that was comparatively more with other formulations, indicating that cNGR-PEG-PTX-NPs could more effectively inhibit tumor growth. As a consequence, the cNGR-PEG-PTX-NPs play a key role in enhancing tumor therapeutic efficiency for treatment of CD13 receptor specific solid tumor.

Citation Format: Dr. Madhu Gupta, Sr., Dr. Vikas Sharma, Prof. G.P. Agrawal, Prof. S.P. Vyas. Cyclic NGR peptide functionalized PEG-PLGA nanoparticles as dual-targeting carrier for site specific antitumor drug delivery. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A31.
Abstract A32: Cell autonomous and cell non-autonomous roles of p75 neurotrophin receptor (p75NTR) in glioma invasion
Authors: Alshehri Mana , Ahn Bo Young , Wang Xiuling , Tanveer Shiekh , Chan Jennifer , Senger Donna L , Robbins Stephen M
Published: May 2016

Human glioblastoam is a heterogeneous tumor composed of tumor cells and a small population known as brain tumor initiating cells (BTICs) or glioblastoma stem-like cells. BTICs appear to drive tumor progression, underlie therapeutic resistance and have been highlighted as therapeutic targets for patients with malignant glioma. The ability of glioma cells to invade into the surrounding brain parenchyma is a major clinical issue rendering glioblastoma incurable by conventional therapies. In a previous study, we found that the p75 neurotrophin receptor (p75NTR) significantly enhanced invasion and migration of genetically distinct glioma by a cell autonomous mechanism. In addition, p75NTR was frequently observed in a highly invasive population of cells from freshly resected patient specimens. Importantly, p75NTR was found to mediate glioma invasion by neurotrophin-dependent regulated intramembrane proteolysis (RIP). Blocking of p75NTR proteolysis by the generation of cleavage-resistance mutants, or treatment of animals bearing p75NTR-postive intracranial tumors with γ-secretase inhibitors, significantly inhibited glioma invasion and prolonged survival. Using a large panel of patient-derived-BTICs we have investigated the role of p75NTR in the stem-like compartment. Here we investigate the biological effects of p75NTR down-regulation on glioma derived BTICs. Immunocytochemical studies western blot analysis reveal that p75NTR is variably expressed on BTICs and that treatment with γ-secretase inhibitors significantly decreases BTIC invasion in 3D cultures in vitro. Down-regulation of p75NTR using shRNA significantly decreases BTICs invasion, proliferation and self-renewal ability. Moreover, p75NTR was present on as a component of BTIC-derived extracellular vesicles (EVs) that are implicated in tumor cell invasion through a cell non-autonomous mechanism. We found that p75NTR containing EVs promote invasion of non-invasive glioma cells. The composition of p75NTR containing EVs and their roles in glioma invasion are currently been investigated.

Citation Format: Mana Alshehri, Bo Young Ahn, Xiuling Wang, Shiekh Tanveer, Jennifer Chan, Donna L Senger, Stephen M Robbins. Cell autonomous and cell non-autonomous roles of p75 neurotrophin receptor (p75NTR) in glioma invasion. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A32.
Abstract B12: GABP selectively binds and activates the mutant TERT promoter across multiple cancer types
Authors: Bell Robert J.A , Rube H. Tomas , Kreig Alex , Mancini Andrew , Fouse Shaun F. , Nagarajan Raman P. , Choi Serah , Hong Chibo , He Daniel , Pekmezci Melike , Wiencke John K. , Wrensch Margaret R. , Chang Susan M. , Walsh Kyle M. , Myong Sua , Song Jun S. , Costello Joseph F.
Published: May 2016

Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent mutations in the TERT promoter specific to two nucleotide positions. The common mutation sites, G228A and G250A, may create de-novo ETS family transcription factor binding sites, but the precise mechanism of how these mutations confer increased TERT expression has been elusive. Here, we demonstrate the de-novo ETS motif to be critical for mutant TERT activation by site directed mutagenesis. A focused siRNA screen of the many ETS transcription factors expressed in GBM identifies GABPA as the single ETS factor to selectively regulate the mutant but not the wild type TERT promoter. Single molecule binding assays and ChIP-qPCR analysis reveal that GABPA is exclusively recruited to the mutant allele in vitro and in vivo respectively. Furthermore, this allelic recruitment is consistent across four tested cancer types, highlighting a shared mechanism underlying mutant TERT promoter activation. Tandem flanking native ETS motifs critically cooperate with these mutations to activate TERT, likely by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression and may provide a novel therapeutic target for multiple cancers.

Citation Format: Robert J.A Bell, H. Tomas Rube, Alex Kreig, Andrew Mancini, Shaun F. Fouse, Raman P. Nagarajan, Serah Choi, Chibo Hong, Daniel He, Melike Pekmezci, John K. Wiencke, Margaret R. Wrensch, Susan M. Chang, Kyle M. Walsh, Sua Myong, Jun S. Song, Joseph F. Costello. GABP selectively binds and activates the mutant TERT promoter across multiple cancer types. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B12.
Abstract B22: Focal brain radiation induces systemic lymphopenia in an animal model
Authors: Piotrowski Anna F. , Velarde Esteban , Grossman Stuart
Published: May 2016

Background: Approximately half of patients with solid tumors develop severe and prolonged lymphopenia after beginning standard radiation and this lymphopenia is associated with shortened survival. An animal model to understand the mechanisms behind radiation-induced lymphopenia has not previously been reported.

Methods: Using the small animal radiation research platform (SARRP) C57BL/6 and BALB/c mice approximately 7-12 weeks old received focal brain irradiation with prolonged and abbreviated schemes: 2 Gy x 30 fractions and 4 Gy x 10 fractions. Blood was collected weekly via peripheral tail vein. Lymphocytes were labelled with antibodies to CD3, CD4, CD8 and CD45 and analyzed by Hemavet, Flow Cytometry and TruCount.

Results: In all four groups (n=12) - C57BL/6 and BALB/c mice receiving prolonged and abbreviated schemes: 2 Gy x 30 fractions and 4 Gy x 10 fractions - lymphopenia was achieved but not sustained. C57BL/6 and BALB/c mice total lymphocyte counts decreased by 72% and 63% of baseline respectively, after 6 weeks of radiation. C57BL/6 and BALB/c mice total lymphocyte counts decreased by 85% and 87% of baseline respectively, after 2 weeks of radiation. Within 3 weeks of the completion of radiation, counts returned to 60-80% of baseline. All animals had a similar magnitude of change in total lymphocyte counts.

Conclusion: This animal model is a practical way to study the reduction in lymphocytes related to radiation. CD4 counts in BALB/c mice receiving prolonged radiation show a linear decline. Future immunology studies should assess T cell subsets and cytokines. The clinically observed phenomenon persistent radiation-induced lymphopenia is challenging to model in mice.

Citation Format: Anna F. Piotrowski, Esteban Velarde, Stuart Grossman. Focal brain radiation induces systemic lymphopenia in an animal model. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B22.
Abstract IA05: Evolution of glioblastoma subtypes
Authors: Michor Franziska
Published: May 2016

To understand the relationships between the non-GCIMP glioblastoma (GBM) subgroups, we performed mathematical modeling to predict the temporal sequence of driver events during tumorigenesis. The most common order of evolutionary events is 1) chromosome (chr) 7 gain and chr10 loss, followed by 2) CDKN2A loss and/or TP53 mutation, and 3) alterations canonical for specific subtypes. We then developed a computational methodology to identify drivers of broad copy number changes, identifying PDGFA (chr7) and PTEN (chr10) as driving initial nondisjunction events. These predictions were validated using mouse modeling, showing that PDGFA is sufficient to induce proneural-like gliomas and that additional NF1 loss converts proneural to the mesenchymal subtype. We further performed integrated genomic and epigenetic profiling of patient-derived cell lines to identify further genes driving subtype transformation as well as alterations in the three-dimensional architecture of the GBM genome during subtype changes. Our computational methodologies can be applied to study the evolutionary dynamics of other cancer types.
Abstract IA19: Modeling blood-CNS barriers in zebrafish
Authors: Umans Robyn A. , Henson Hannah E. , Parupalli Chaithanyarani , Ju Bensheng , Taylor Michael R.
Published: May 2016

The blood-brain barrier (BBB) plays an important role in the treatment of brain tumors. Yet, a comprehensive understanding of brain tumor vasculaturization has been hampered by difficulties in observing this process in vivo. Recently, we have generated several models of brain tumors in zebrafish. To visualize the vascularization of these tumors, we generated transgenic zebrafish lines to serve as in vivo reporters of brain tumor vasculature. We show that our BBB transgenic line drives expression specifically in brain endothelial cells and not in the vasculature of peripheral tissues or circumventricular organs. Using time-lapse confocal microscopy, we find that barriergenesis (i.e. the initiation of BBB development) occurs immediately as new vessels sprout into the brain parenchyma. Using a combination of genetic and chemical tools, we demonstrate that canonical Wnt signaling, but not VEGF signaling, is essential for barriergenesis. These results indicate that CNS angiogenesis and barriergenesis occur simultaneously, but require distinct signals for proper formation. Furthermore, we created a complementary transgenic line that drives expression in fenestrated endothelium, a hallmark of brain tumor vasculature. The combination of these transgenic lines along with our newly developed tumor models will allow us to visualize the complexities of brain tumor vascularization in a live animal model.

Citation Format: Robyn A. Umans, Hannah E. Henson, Chaithanyarani Parupalli, Bensheng Ju, Michael R. Taylor. Modeling blood-CNS barriers in zebrafish. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA19.
Abstract IA24: Understanding and tackling differing vascular niches in glioma
Authors: Bergers Gabriele
Published: May 2016

Glioblastoma multiforme (GBM) is the most belligerent adult brain tumor, which is defined by its aggressive growth due to uncontrolled cellular proliferation, resistance to apoptosis, diffuse infiltration and invasion, propensity for necrosis and hypoxia, and vigorous angiogenesis. Recurrence of these invasive tumors is inevitable despite advanced multimodal therapy with surgery followed by radiation and temozolomide treatment resulting in a dismal median survival of beyond one year. A recent milestone in glioma research has been the revelation that therapies targeting other cell types besides tumor cells; i.e., the cell constituents of the vascular niche can convey substantial improvements in radiographic response, progression-free survival, and quality of life. The changing perspective on the environment as a functional contributor represents a profound shift in the approach to biology and therapeutic decisions in GBM. Here, we describe paracrine signaling pathways of the differing vascular niches that regulate angiogenesis or tumor invasiveness and present therapeutic modalities to target those to more efficiently block diffuse and angiogenic GBM growth.

Citation Format: Gabriele Bergers. Understanding and tackling differing vascular niches in glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA24.
Abstract B1-12: RNA Architect: High performance tools to exhaustively detect cancer-specific structural events in RNA sequencing data
Authors: Arnold Roland Chrisitian , Rosic Andrej , Hayes Reid JP , Shlien Adam
Published: May 2016

The transcriptomes of cancer cells differ structurally and numerically from normal tissue and between different types of cancer. However, a comprehensive large-scale analysis of structural transcriptomic events has been intractable so far due to computational limitations and the lack of an integrative software tool to detect a complete list of events. We developed an optimized computation pipeline, named RNA Architect, which enables the detection of such events from RNA sequencing data for thousands of cancer samples. RNA Architect detects events by discordant read pair and split-read analysis down to the resolution of individual breakpoints. Beside different kinds of fusion events (as in-frame, out of frame, fusions to intergenic regions), it reports a comprehensive overview of other transcriptional events including specific and novel splice-forms, inversions, cryptic and alternative splice sites, exon skips, exon re-usages, and early polyadenylation sites.

In this poster, we describe the individual steps of the algorithm as well as our latest benchmarking results on a compilation of literature curated gene fusions: the approach shows a high sensitivity and recovers 92% of known fusion events. We also describe the post-processing of the data, which enables us to delineate relevant events from non-cancer specific ones and noise. We especially discuss optimizations implemented to run the software efficiently on a state of the art compute cluster. These optimizations enable the computation of a large amount of samples in a reasonable time frame (~ 8h on a 100 CPU system for the core split-read algorithm and ~3 hours for the discordant pair analysis on a 50 CPU system per sample).

The high performance of the pipeline allows generating a comprehensive catalogue of all transcriptional events from large sets of cancer samples. RNA Architect is also fast enough to be used in time critical clinical settings as a potential diagnostic tool.

Citation Format: Roland Chrisitian Arnold, Andrej Rosic, Reid JP Hayes, Adam Shlien. RNA Architect: High performance tools to exhaustively detect cancer-specific structural events in RNA sequencing data. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-12.
Abstract B1-27: Optimal combined anticancer therapy that can overcome cell-type specific drug resistance of breast cancer
Authors: Choi Minsoo , Cho Kwang-Hyun
Published: May 2016

Breast cancer is a complex disease associated with various genomic alterations that influence the dynamical change of signaling network. The inherent heterogeneous characteristics of breast cancer cells often result in variable anti-cancer drug resistance. Despite the recent progress of targeted cancer therapy, the underlying mechanism of such variable drug resistance still remains unclear and needs to be investigated. To tackle this problem with respect to a breast cancer signaling network, we have reconstructed differential breast cancer singling networks by integrating various genomic data of breast tumors and analyzed their state transition dynamics through perturbation simulations that mimick various anti-cancer drug treatments. We then categorized heterogeneous breast cancer cell types into three groups: sensitive, moderate, or resistant to drugs. For each group, we identified a distinct core-signaling mechanism underlying the drug resistance on the basis of attractor landscape analysis. Finally, we have identified an optimal drug combination that can maximize cell death regardless of heterogeneous breast cancer cell types. Our study shows that the attractor landscape analysis of a breast cancer signaling network can unravel the hidden mechanism underlying individual variation in drug responses and provide a new therapeutic strategy that can overcome variable drug resistance.

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2014R1A2A1A10052404, 2013M3A9A7046303, and 2010-0017662).

Citation Format: Minsoo Choi, Kwang-Hyun Cho. Optimal combined anticancer therapy that can overcome cell-type specific drug resistance of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-27.
Abstract B1-58: Computational modeling provides new insights into KRAS mutant-specific responses to targeted therapy
Authors: Stites Edward C.
Published: May 2016

Emerging data suggest different activating Ras mutants may have different biological behaviors. The most striking example may be in colon cancer, where activating KRAS mutations generally indicate a lack of benefit to treatment with cetuximab, with the activating KRAS G13D mutation an apparent exception. It is unclear why patients with KRAS G13D would respond to cetuximab; KRAS G13D shares the same general biochemical defects as the other oncogenic KRAS mutants. Here, a previously developed mathematical model of the biochemical reactions that regulate Ras signaling is used to investigate this problem. The purpose of the analysis is to determine whether known mechanisms of Ras signaling allow similar, but different, Ras mutants to respond differently to the same inhibitor, and to determine if the known biochemical properties of the G13D Ras mutant are consistent with increased sensitivity to upstream inhibition. Computational analysis of the mathematical model finds that differential response to upstream inhibition between different Ras mutants is indeed consistent with known mechanisms of Ras biology. Moreover, modeling demonstrates that the subtle biochemical differences between the responsive G13D mutant and the non-responsive G12D and G12V mutants are sufficient to explain the different responses to cetuximab. Simulations further identify differences in wild-type Ras signaling as the key difference between the mutants. The analysis suggests the elevated Km for the Ras GAP reaction on the G13D mutant is the biochemical property that most contributes to differences in wild-type Ras signaling. The identification of a single parameter that influences sensitivity to a targeted therapy is significant in that it suggests an approach to evaluate other, less common, Ras mutations for their anticipated response to cetuximab.

Note: This abstract was not presented at the conference.

Citation Format: Edward C. Stites. Computational modeling provides new insights into KRAS mutant-specific responses to targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-58.
Abstract B1-60: Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers
Authors: Orlando David A. , McKeown Michael R. , Chen Mei Wei , Collins Cindy , Guenther Matthew G. , Fritz Christian C.
Published: May 2016

Identifying biomarkers that predict clinical responses to anticancer therapies is an important challenge in oncology. A desirable biomarker is a cell-identifying feature that can distinguish between drug responsive and unresponsive cell types. Most of the best studied biomarkers are gene mutations or copy-number changes, where the genomic alteration is the key defining feature. However, not all differences in clinical responses can be attributed to genetic differences. Therefore, it is critical that we identify other cellular features that can predict response. A recently described epigenomic feature, termed super-enhancer (SE), defines key cell identity and disease genes and SEs are effectors of initiating and maintaining cell type-specific gene expression programs. In this work we generate super-enhancer maps across multiple cancer cell lines and connect those maps to response to different drug treatments. We show that super-enhancers can be used as biomarkers to predict response to drugs across multiple cell-line models of cancer. This work suggests that interrogating epigenomic features, and in particular super-enhancers, can be a powerful biomarker discovery platform and can enable rational patient selection and therapeutic strategies.

Citation Format: David A. Orlando, Michael R. McKeown, Mei Wei Chen, Cindy Collins, Matthew G. Guenther, Christian C. Fritz. Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-60.
Abstract B2-25: DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers
Authors: Liu Yu , Liu Yang , Xiao Zhengtao , Yang Xuerui
Published: May 2016

Context-dependent DNA methylation plays a critical role in regulating gene transcription, thereby serving as an important epigenetic marker or regulator in many biological activities such as pluripotency, development, and complex diseases such as cancer. However, previously in most of the de novo reconstructions of cancer type-specific transcription regulatory networks (TRN), DNA methylation has rarely been taken into account as a significant factor in regulating transcription factor activity and controlling gene expression. The present study was set to systematically assess the involvement of DNA methylation in transcription regulatory circuitry in cancer. We took advantages of the multi-dimensional profiling data of DNA methylations and gene expressions in tumor samples of different cancers in The Cancer Genome Atlas (TCGA) consortium, and developed an integrative analysis pipeline based on conditional mutual information theory, to quantify the cooperative regulatory effects of CpG site methylations and transcription factors on gene expressions, in a genome-wide scale. Our analysis showed that DNA methylation and transcription factors indeed control gene expressions often in duet. To map the interplay between these two major defining factors of gene expression, DNA Methylation-dependent Transcription Regulatory Network (MeTRN), the first of its kind, was assembled for each of 19 major cancer types in TCGA. MeTRN provides a comprehensive view specifically on DNA methylation-dependent transcription events in each cancer type, and has been largely validated by public ChIP-seq and DNaseI-seq data. Comparison of these networks across cancer types showed that context-specificity of transcriptional circuits can be largely attributed to the context-dependent nature of DNA methylation patterns. Therefore, by assembling the cooperative effects of transcription factors and DNA methylations on gene transcription, MeTRN recapitulates an epigenetic scheme that implements dynamics of transcription regulatory circuitry across cancers via context-dependent DNA methylation marks. Supported by extensive cross-validations and experimental evidence, this epigenetically marked and dynamic transcription regulatory circuitry serves as a new basis for further mechanistic studies of gene expression dysregulations in cancers.

Citation Format: Yu Liu, Yang Liu, Zhengtao Xiao, Xuerui Yang. DNA methylation-dependent transcription regulatory networks elucidate dynamics of transcription regulatory circuitry in cancers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-25.
Abstract B2-28: The development of an individualized Boolean network model for targeted anticancer therapy of glioblastoma
Authors: Lee Hwang-Yeol , Cho Kwang-Hyun
Published: May 2016

Understanding the complexity of a cancer signaling network contributed to the discovery of potential targets for therapeutic intervention. Mathematical and computational models have been developed and investigated to predict the molecular dynamics during cancer development and drug treatment. Recent studies analyzing large-scale patient data, however, showed that genetic alterations are dramatically different among patients even for the same type of cancer, and that different therapeutic strategies should be employed for the patients. To resolve this problem using Boolean network modeling and analysis, we have integrated genome-wide data of glioblastoma patients from TCGA database and constructed an individualized network model for each patient. We defined three attractor states that represent different cell fates: proliferation, cell cycle arrest, and apoptosis. We then applied the information of patient-specific genetic alterations to the Boolean model by adjusting the interaction weights of the mutated molecules, and investigated the change of attractors for each patient. Finally, we have investigated the targeted therapy for each patient by performing perturbation analysis of the individualized network model to find the optimal drug combination. Together, our study provides a new insight into the impact of genetic alterations on the drug responses and the patient-specific therapeutic strategies.

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2014R1A2A1A10052404, 2013M3A9A7046303, and 2010-0017662) and by the KUSTAR-KAIST Institute, Korea, under the R&D program supervised by the KAIST.

Citation Format: Hwang-Yeol Lee, Kwang-Hyun Cho. The development of an individualized Boolean network model for targeted anticancer therapy of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-28.
Abstract B2-44: Structure-based design of inhibitory peptides for LRP6
Authors: Rismani Elham , Rahimi Hamzeh , Azadmanesh Kayhan , Arab Shahriar , Karimipoor Morteza , Teimoori-Toolabi Ladan
Published: May 2016

Wnt signaling pathway plays a major role in regulation of cell proliferation, migration, tissue homeostasis, tumor progression and cancer. This pathway can be antagonized by DKK proteins, which disrupt the intiationary complex (Frizzled-LRP5/6 complex). Nowadays, use of peptides in order to target tumor cells is attracting much attention. In this study, a computational protocol is presented to structural design of inhibitory peptides aginst Low-density lipoprotein receptor-related protein 6 (LRP6) as receptor. Firstly, natural ligand of LRP6 divided to 12 fragments as peptide derivatives. Then, molecular dynamics simulations used for structural energy minimization by means of Gromacs 4.5.4. The binding affinities of designed peptides were investigated via molecular docking using ClusPro webTool. Finally, stability and binding free energy of peptides were calculated by FoldX software. The results showed that four of designed peptides had the highest affinity to interact with the receptor and can be considered as candidates for inhibition of wnt signaling pathway through LRP5/6 receptor.

Citation Format: Elham Rismani, Hamzeh Rahimi, Kayhan Azadmanesh, Shahriar Arab, Morteza Karimipoor, Ladan Teimoori-Toolabi. Structure-based design of inhibitory peptides for LRP6. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-44.
Abstract B2-45: Uncovering coordinated regulation of transcription factors by microRNAs using integrated network models
Authors: Gosline Sara JC , Gurtan Allan M. , JnBaptiste Courtney K. , Bosson Andrew , Milani Pamela , Dalin Simona , Matthews Bryan , Yap Yoon Sing , Sharp Phillip A. , Fraenkel Ernest
Published: May 2016

MicroRNAs (miRNAs) are small non-coding RNAs that play a significant role in development and cancer but induce only moderate repression of direct messenger RNA (mRNA) targets, suggesting that they coordinate with other modes of cellular regulation to affect cellular phenotype. In this work we exhaustively profile the transcriptional and post-transcriptional regulatory changes between an isogenic pair of murine fibroblast cell lines with and without Dicer, an enzyme required for miRNA processing. Through quantitative analysis of diverse high-throughput datasets collected from both cell lines, we were able to decouple transcriptional from post-transcriptional changes reflected in mRNA expression changes between cells with and without miRNAs.

We present three major findings. First, we find that direct miRNA-mRNA interactions have a limited impact on gene expression changes upon Dicer deletion when compared to changes at transcription. We then introduce an integrative graphical network approach to identify specific transcription factors that explain the observed changes in gene expression upon loss of Dicer. Validation of this computational model via transcription factor over-expression reveals a subset of the miRNA-mediated transcriptional program that is activated upon Dicer loss, confirming that transcriptional networks amplify the effects of miRNAs. Lastly, we use this network to examine coordination between transcriptional and post-transcriptional regulation. We identify numerous coherent and in-coherent feed-forward loops, network motifs that have been alluded to but only minimally studied in the context of microRNAs and transcription factors, and find that genes regulated within feed-forward loops by microRNAs and transcription factors exhibit distinct properties in development.

In summary, our work illustrates how transcriptional networks amplify the effects of microRNAs. We show coordinated regulation of transcription factors by microRNAs that suggests that most gene expression changes attributed to microRNAs in diseases such as cancer are due to changes in transcription rather than microRNA-mediated degradataion. As such, this work has the potential to reframe future studies of microRNAs in the context of cancer by shifting the focus to understanding the impact of microRNAs on transcription factors.

Citation Format: Sara JC Gosline, Allan M. Gurtan, Courtney K. JnBaptiste, Andrew Bosson, Pamela Milani, Simona Dalin, Bryan Matthews, Yoon Sing Yap, Phillip A. Sharp, Ernest Fraenkel. Uncovering coordinated regulation of transcription factors by microRNAs using integrated network models. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-45.
Abstract PR09: Extracellular stiffness cues drive spatial reorganization of the genome to globally constrain RNA abundance
Authors: Bainer Russell , Yui Yoshihiro , Mumenthaler Shannon , Mallick Parag , Liu Lin , Wu Hua-Jun , Podlaha Ondrej , Michor Franziska , Liphardt Jan , Licht Jonathan , Weaver Valerie
Published: May 2016

The stiffness of the extracellular matrix (ECM) drives mechanosignaling that regulates tissue development and malignancy. We previously showed that a stiff ECM disrupts tissue organization and enhances malignant progression by inducing cell invasion and migration. However, the specific transcriptional and molecular events in which mechanotransduction directs these phenotypes are not well understood. To clarify this process, we used a combination of genome-scale approaches to monitor changes in gene expression and protein abundance as a function of acinar morphogenesis and tissue homeostasis in three dimensional extracellular matrix hydrogels with tunable stiffness. Elevated ECM stiffness perturbed tissue homeostasis and reverted the transcriptional phenotype of differentiated mammary acini to resemble that observed in rapidly proliferating nonpolarized mammary cell aggregates. These findings suggest that tissue tension induces cellular changes that directly reflect higher-order tissue organizational states. We found that these changes involve the spatial rearrangement of peripheral chromatin, and that the expression levels of multiple histone deacetylases increase in organized tissues concurrently with elevated nuclear heterochromatin content, an effect that is abrogated in rigid ECM conditions. We support these observations by mapping mechanoresponsive peripheral heterochromatin elements via ChIPseq, enabling us to directly identify dynamic regions containing genes whose transcriptional activity is responsive to mechanical cues. Finally, using a combination of genomic, imaging, and molecular biology techniques we demonstrated that ECM compliance and tissue organization significantly influences global RNA abundance. Notably, this model presents formidable conceptual and practical challenges for the interpretation of genomic data. Collectively, this work indicates that tissue organization is critically dependent on the cellular mechanical environment, which qualitatively and quantitatively shapes the epigenetic and transcriptional landscape by mechanisms that have not yet been elucidated.

Note: This abstract was not presented at the conference.

Citation Format: Russell Bainer, Yoshihiro Yui, Shannon Mumenthaler, Parag Mallick, Lin Liu, Hua-Jun Wu, Ondrej Podlaha, Franziska Michor, Jan Liphardt, Jonathan Licht, Valerie Weaver. Extracellular stiffness cues drive spatial reorganization of the genome to globally constrain RNA abundance. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR09.
Abstract B42: A two-lncRNA signature in serous exosomes serves as a new biomarker for colorectal cancer diagnosis
Authors: Qi Peng , Dong Lei , Lin Wanrun , Zhou Xiaoyan , Du Xiang
Published: May 2016

Background: Many studies have shown that long non-coding RNAs (lncRNAs) participate in the initiation and development of colorectal cancer (CRC). We previously reported that lncRNAs can be detected and are stable in serum. Exosomes (EXOs) are small (30 to 100 nm) membrane-bound particles that are released from normal, diseased, and neoplastic cells and are present in blood and other bodily fluids. EXOs contain a variety of molecules including signal peptides, mRNA, microRNA, and lipids. However, it is unclear if lncRNAs in serous EXOs represent a novel marker to detect CRC.

Methods: Total RNA and serous EXO RNA were isolated from serum of 60 CRC patients, 60 age- and sex-matched healthy subjects. We measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in EXO RNA samples. The putative lncRNA markers identified in the training set (30 CRC patients and 30 healthy subjects) were verified in the test set (another 30 CRC patients and 30 healthy subjects). We further analyzed the putative lncRNA markers in serum total RNA samples.

Results: In the training set, 16 lncRNAs were detectable in serous EXOs, and the expression levels of 7 lncRNAs were significantly different between healthy samples and CRC samples (p<0.05). Stepwise regression analysis showed that the combination of prostate cancer associated 3 (PCA3) and breast cancer anti-estrogen resistance 4 (BCAR4) provided the greatest predictive ability, with an AUC of 0.896 (95% CI: 0.794-0.921, p=0.029). Using the same serum samples, we compared the AUC values of these two lncRNAs in EXO with those in total RNA samples. The AUC values of our serous EXO two-lncRNA signature were markedly higher than those of serum signature (AUC=0.759, 95% CI: 0.696-0.853) for discriminating CRC patients from controls. The predictor was remarkably stable when applied to the test set comprising 30 CRC patients and 30 matched controls, with an AUC of 0.875. The AUC values of the serous EXO two-lncRNA signature for the test set were also markedly higher than those of serum signature (AUC=0.742 95% CI: 0.653-0.801) for discriminating CRC patients from controls. The results indicated that the two-lncRNA signature in serous EXO is an accurate biomarker for CRC diagnosis

Conclusions: The PCA3 and BCAR4 signature in serous EXOs may facilitate the detection of CRC and serve as the basis for further studies of the clinical value of circulating lncRNAs in maintaining surveillance and forecasting prognosis.

Citation Format: Peng Qi, Lei Dong, Wanrun Lin, Xiaoyan Zhou, Xiang Du. A two-lncRNA signature in serous exosomes serves as a new biomarker for colorectal cancer diagnosis. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr B42.