Bulletin of the American Physical Society
APS March Meeting 2013
Volume 58, Number 1
Monday–Friday, March 18–22, 2013; Baltimore, Maryland
Session Y45: Focus Session: Physics of Cancer II |
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Sponsoring Units: DBIO Chair: Larry Nagahara, National Institutes of Health Room: Hilton Baltimore Holiday Ballroom 4 |
Friday, March 22, 2013 8:00AM - 8:12AM |
Y45.00001: Collective Behavior of Brain Tumor Cells: the Role of Hypoxia Evgeniy Khain, Mark Katakowski, Scott Hopkins, Alexandra Szalad, Xuguang Zheng, Feng Jiang, Michael Chopp We consider emergent collective behavior of a multicellular biological system. Specifically we investigate the role of hypoxia (lack of oxygen) in migration of brain tumor cells [1]. We performed two series of cell migration experiments. The first set of experiments was performed in a typical wound healing geometry: cells were placed on a substrate, and a scratch was done. In the second set of experiments, cell migration away from a tumor spheroid was investigated. Experiments show a controversy: cells under normal and hypoxic conditions have migrated the same distance in the ``spheroid'' experiment, while in the ``scratch'' experiment cells under normal conditions migrated much faster than under hypoxic conditions. To explain this paradox, we formulate a discrete stochastic model for cell dynamics [1,2]. The theoretical model explains our experimental observations and suggests that hypoxia decreases both the motility of cells and the strength of cell-cell adhesion. The theoretical predictions were further verified in independent experiments [1]. \\[4pt] [1]. E. Khain, M. Katakowski, S. Hopkins, A. Szalad, X.G. Zheng, F. Jiang, M. Chopp, Physical Review E 83, 031920 (2011). \\[0pt] [2]. E. Khain, C. M. Schneider-Mizell, M. O. Nowicki, E. A. Chiocca, S. E. Lawler and L. M. Sander, EPL (Europhysics Letters) 88, 28006 (2009). [Preview Abstract] |
Friday, March 22, 2013 8:12AM - 8:24AM |
Y45.00002: Rapid evolution of drug resistance of multiple myeloma in the microenvironment with drug gradients Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Ariosto Silva, Robert Gatenby, John Kim, Nader Pourmand, Robert Austin, James Sturm Drug resistance in cancer is usually caused by the spatial drug gradients in tumor environment. Here, we culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region for 12 days. The myeloma cells grew rapidly and formed 3D colonies in the regions with less drug concentration. However, we have seen emergent colonies forming in regions with drug concentration above the minimal inhibitory concentration in less than one week. Once the cells have occupied the regions with less drug concentration, they tend to migrate toward the regions with higher drug concentration in a collective behavior. To characterize their resistance, we collect them from this microfluidic system, for further analysis of the dose response. We find that the IC50 (drug concentration that inhibits 50\% of controlled population) of the cells, undergone a drug gradient, increase 16-fold of the wildtype cells. We further discover that these resistant cells express more Multidrug Resistance (mdr) protein, which pumps out the drugs and causes drug resistance, than the wildtype. Our current works on RNA-sequencing analysis may discover other biomolecular mechanisms that may confer the drug resistance. [Preview Abstract] |
Friday, March 22, 2013 8:24AM - 8:36AM |
Y45.00003: Hierarchy of Gene Expression as a Biomarker for Breast Cancer Prognosis Man Chen Cancer is a dedifferentiation of healthy cellular and genetic processes. At the same time, specific oncological pathways are activated in the cancer state [1]. Cancer metastasis exposes cancer cells to a variety of microenvironments, in which physics of evolution suggests modularity is a relevant order parameter [2]. We were thus motivated to examine the structure in gene and tissue networks of breast cancer patients. We studied the relation between metastasis and breast cancer network structure. We found that hierarchy of cancer networks distinguishes non-metastatic from metastatic patient populations. We also found that for cancer-associated genes, likelihood of metastasis is correlated with increased network hierarchy. Conversely for tissue networks using all gene data, reduced network structure is correlated with likelihood of metastasis. We suggest hierarchy of gene expression may be useful as a biomarker for breast cancer breast cancer metastasis and recurrence. For those patients with reduced structure, which is at least 5\% of the patient population, this biomarker provides a strong signal for likelihood of cancer metastasis.\\[4pt] [1] Paul Davis, Physical Biology vol (2011) page\\[0pt] [2] Jun Sun Phys. Rev. Lett vol (2007) page [Preview Abstract] |
Friday, March 22, 2013 8:36AM - 8:48AM |
Y45.00004: Ultrasensitive Mirco-Hall Detector for Enumeration and Molecular Profiling of Rare Cells Changwook Min, David Issadore, Jaehoon Chung, Huilin Shao, Monty Liong, Arezou A. Ghazani, Cesar M. Castro, Ralph Weissleder, Hakho Lee We have recently developed a miniaturized microfluidic chip-based technology, the micro-Hall detector (uHD), that can perform rapid, highly sensitive, and quantitative measurement of individual cells in unprocessed biological samples. The uHD detects the Hall voltage induced by magnetic moments of cells in-flow that have been immunomagnetically tagged with magnetic nanoparticles (MNPs) and bio-orthogonal chemistry. The entire assay is performed on a single microfluidic chip with minimal sample preparation to avoid sample loss and to simplify assay procedure, eliminating the need for any washing and purification steps, and thereby allows cellular diagnostics to be conducted in point-of-care clinical settings. We also demonstrated simultaneous detection of heterogeneous biomarkers on individual cells by targeting different cellular markers with a panel of MNPs. The quantity of each MNP type, and hence the expression level of a target biomarker in a single cell, could be obtained using the particles' distinctive magnetization properties. The clinical use of the uHD was explored by the detection of circulating tumor cells (CTCs) in whole blood of 20 ovarian cancer patients, and drug treatment efficacy was monitored in a mouse tumor model. [Preview Abstract] |
Friday, March 22, 2013 8:48AM - 9:00AM |
Y45.00005: Miniaturized holographic imaging system for real-time cellular detection Jun Song, Hyungsoon Im, Monty Liong, Lioubov Fexon, Misha Pivovarov, Ralph Weissleder, Hakho Lee We herein present a miniaturized holographic imaging system for high throughput cellular detection. The system consists of an imager chip with a microfluidic channel built on top. Clinical samples (e.g., blood) are introduced into the fluidic channel, and holographic images of cells are recorded by the imager chip. We then perform computational reconstruction of original cell images, retrieving both the intensity and phase information. For fast image reconstruction, we have implemented parallel computing software and utilized multicore GPU (graphics processing unit) chips. The resulting imaging system enabled high throughput cellular detection; up to 1000 cells/$\mu$L could be imaged over a wide detection area (20 mm$^{2}$), and cellular images could be reconstructed in real time (20 frames/sec). Furthermore, assays can be performed without extra dilution and washing steps, which significantly simplifies the diagnosis process. This cost-effective, real-time holographic imaging system can be used for target cell detection in point-of-care applications. [Preview Abstract] |
Friday, March 22, 2013 9:00AM - 9:12AM |
Y45.00006: Rapid detection and profiling of rare cancer cells with a portable holographic imaging system Hyungsoon Im, Jun Song, Monty Liong, Lioubov Fexon, Misha Pivovarov, Ralph Weissleder, Hakho Lee We herein present the detection and molecular profiling of rare cancer cells, using a chip-based holographic imaging system. In this approach, target cancer cells are labeled with molecular-specific microbeads. Such labeling enables 1) a reliable differentiation between cancer cells and host cells (e.g., leukocytes); and 2) quantitative profiling of target marker expression through bead-counting. A new algorithm for digital image reconstruction and bead counting was developed as well to facilitate the assay. The developed system were able to accurately count more than thousands of beads and cells in a single image. Importantly, the assay could be performed without any dilution or washing steps, minimizing cell loss and simplifying the assay procedure. By counting the number of beads attached on cells, we could also measure the expression levels of different cancer markers, which showed good agreement with profiling results by flow cytometry and fluorescence microscopy. This cost-effective, portable, flow-based holographic imaging system is applicable to detecting rare cancer cells in a large volume of blood samples for point-of-care applications. [Preview Abstract] |
Friday, March 22, 2013 9:12AM - 9:48AM |
Y45.00007: A single-molecule view of gene regulation in cancer Invited Speaker: Daniel Larson Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. Steroid receptors coordinate a diverse range of responses in higher eukaryotes and are involved in a wide range of human diseases, including cancer. Steroid receptor response elements are present throughout the human genome and modulate chromatin remodeling and transcription in both a local and long-range fashion. As such, steroid receptor-mediated transcription is a paradigm of genetic control in the metazoan nucleus. Moreover, the ligand-dependent nature of these transcription factors makes them appealing targets for therapeutic intervention, necessitating a quantitative understanding of how receptors control output from target genes. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single gene and follow dynamic synthesis of RNA from the activated locus. The response delay is a measure of time required for chromatin remodeling at a single gene. [Preview Abstract] |
Friday, March 22, 2013 9:48AM - 10:00AM |
Y45.00008: Non-covalent interactions of the carcinogen (+)-anti-BPDE with exon 1 of the human K-ras proto-oncogene Jorge H. Rodriguez, Christos Deligkaris Investigating the complementary, but different, effects of physical (non-covalent) and chemical (covalent) mutagen-DNA and carcinogen-DNA interactions is important for understanding possible mechanisms of development and prevention of mutagenesis and carcinogenesis. A highly mutagenic and carcinogenic metabolite of the polycyclic aromatic hydrocarbon benzo[$\alpha$]pyrene, namely (+)-anti-BPDE, is known to undergo both physical and chemical complexation with DNA. The major covalent adduct, a promutagenic, is known to be an external (+)-trans-anti-BPDE-N$^2$-dGuanosine configuration whose origins are not fully understood. Thus, it is desirable to study the mechanisms of external non-covalent BPDE-DNA binding and their possible relationships to external covalent trans adduct formation. We present a detailed codon-by-codon computational study of the non-covalent interactions of (+)-anti-BPDE with DNA which explains and correctly predicts preferential (+)-anti-BPDE binding at minor groove guanosines. Due to its relevance to carcinogenesis, the interaction of (+)-anti-BPDE with exon 1 of the human K-ras gene has been studied in detail. [Preview Abstract] |
Friday, March 22, 2013 10:00AM - 10:12AM |
Y45.00009: The Causality of Evolution on Different Fitness Landscapes Saurabh Vyawahare, Robert Austin, Qiucen Zhang, Hyunsung Kim, John Bestoso Evolution of antibiotic resistance is a growing problem. One major reason why most antibiotics fail is because of mutations on drug targets (e.g. essential enzymes). Sequencing of clinically resistant isolates have shown that multiple mutational-hotspots exist in coding regions, which could potentially prohibit the binding of drugs. However, it is not clear whether the appearance of each mutation is random or influenced by other factors. In this paper, we compare evolution of resistance to ciprofloxacin from two distinct but well characterized genetic backgrounds. By combining our recently developed evolution reactor and deep whole-genome sequencing, we show different alleles of $\sigma_s$ factor lead to fixation of different mutations in {\em gyrA} gene that confer ciprofloxacin resistance to bacteria {\em Escherichia coli}. Such causality of evolution in different genes provides an opportunity to control the evolution of antibiotic resistance. [Preview Abstract] |
Friday, March 22, 2013 10:12AM - 10:24AM |
Y45.00010: Evolution of radiation resistance in a complex microenvironment So Hyun Kim, Robert Austin, Monal Mehta, Atif Kahn Radiation treatment responses in brain cancers are typically associated with short progression-free intervals in highly lethal malignancies such as glioblastomas. Even as patients routinely progress through second and third line salvage therapies, which are usually empirically selected, surprisingly little information exists on how cancer cells evolve resistance. We will present experimental results showing how in the presence of complex radiation gradients evolution of resistance to radiation occurs. [Preview Abstract] |
Friday, March 22, 2013 10:24AM - 10:36AM |
Y45.00011: Modeling growth and dissemination of lymphoma in a co-evolving lymph node: a diffuse-domain approach Yao-Li Chuang, Vittorio Cristini, Ying Chen, Xiangrong Li, Hermann Frieboes, John Lowengrub While partial differential equation models of tumor growth have successfully described various spatiotemporal phenomena observed for in-vitro tumor spheroid experiments, one challenge towards taking these models to further study in-vivo tumors is that instead of relatively static tissue culture with regular boundary conditions, in-vivo tumors are often confined in organ tissues that co-evolve with the tumor growth. Here we adopt a recently developed diffuse-domain method to account for the co-evolving domain boundaries, adapting our previous in-vitro tumor model for the development of lymphoma encapsulated in a lymph node, which may swell or shrink due to proliferation and dissemination of lymphoma cells and treatment by chemotherapy. We use the model to study the induced spatial heterogeneity, which may arise as an emerging phenomenon in experimental observations and model analysis. Spatial heterogeneity is believed to lead to tumor infiltration patterns and reduce the efficacy of chemotherapy, leaving residuals that cause cancer relapse after the treatment. Understanding the spatiotemporal evolution of in-vivo tumors can be an essential step towards more effective strategies of curing cancer. [Preview Abstract] |
Friday, March 22, 2013 10:36AM - 10:48AM |
Y45.00012: Computational studies on DNA recognition of novel organic and copper anti-tumor compounds Rafael R. Nascimento, Marcos B. Gon\c{c}alves, Helena M. Petrilli, Ana M. D.C. Ferreira, Emiliano Ippoliti, Jens Dreyer, Paolo Carloni The ability of many organic and coordination compounds to bind to DNA and/or damage cellular structures has been largely exploited in anticancer research. Identifying DNA recognition mechanisms have thus important impact on the chemical biology of gene expression and the development of new drugs and therapies. Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential anti-tumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria [SIL11]. The binding mechanism of the organic and copper(II) complexes [Cu(isaepy)2]2$+$ (1) and [Cu(isaenim)]2$+$ (2) and their modulation at DNA is investigated through theoretical studies. Here we adopted a multi-scale procedure to simulate this large system using molecular docking and classical molecular dynamics. Hybrid Car-Parrinello/Molecular Mechanics calculations were applied to parameterize the copper(II) complexes by using the force matching approach. Free energies of binding are investigated by metadynamics enhanced sampling methods[VAR08]. [SIL11] V. C. da Silveira et. al. JIB 105 (2011) 1692.[VAR08] A. V. Vargiu et. al. Nucl. Acids Res. 36 (2008) 5910. [Preview Abstract] |
Friday, March 22, 2013 10:48AM - 11:00AM |
Y45.00013: The positioning logic and copy number control of genes in bacteria under stress Qiucen Zhang, Robert Austin, Saurabh Vyawahare, Alexandra Lau {\em Escherichia coli} ({\em E. coli}) cells when challenged with sublethal concentrations of the genotoxic antibiotic ciprofloxacin cease to divide and form long filaments which contain multiple bacterial chromosomes. These filaments are individual mesoscopic environmental niches which provide protection for a community of chromosomes (as opposed to cells) under mutagenic stress and can provide an evolutionary fitness advantage within the niche. We use comparative genomic hybridization to show that the mesoscopic niche evolves within 20 minutes of ciprofloxacin exposure via replication of multiple copies of genes expressing ATP dependent transporters. We show that this rapid genomic amplification is done in a time efficient manner via placement of the genes encoding the pumps near the origin of replication on the bacterial chromosome. The de-amplification of multiple copies back to the wild type number is a function of the duration is a function of the ciprofloxacin exposure duration: the longer the exposure, the slower the removal of the multiple copies. [Preview Abstract] |
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