Bulletin of the American Physical Society
APS March Meeting 2014
Volume 59, Number 1
Monday–Friday, March 3–7, 2014; Denver, Colorado
Session G10: Focus Session: Physics of Cancer |
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Sponsoring Units: DBIO Chair: Robert Austin, Princeton University Room: 201 |
Tuesday, March 4, 2014 11:15AM - 11:27AM |
G10.00001: The cytoskeleton significantly impacts invasive behavior of biological cells Anatol Fritsch, Josef K\"as, Kristin Seltman, Thomas Magin Cell migration is a key determinant of cancer metastasis and nerve regeneration. The role of the cytoskeleton for the epithelial-meschenymal transition (EMT), i.e, for invasive behavior of cells, is only partially understood. Here, we address this issue in cells lacking all keratins upon genome engineering. In contrast to prediction, keratin-free cells show a 60{\%} higher deformability compared to less pronounced softening effects for actin depolymerization. To relate these findings with functional consequences, we use invasion and three-dimensional growth assays. These reveal higher invasiveness of keratin-free cells. This study supports the view that downregulation of keratins observed during EMT directly contributes to the migratory and invasive behavior of tumor cells. Cancer cells that effectively move through tissues are softer and more contractile than cells that stay local in tissues. Soft and contractile avoids jamming. Naturally, softness has to have its limits. So neuronal growth cones are too soft to carry large loads to move efficiently through scar tissue, which is required for nerve regeneration. In synopsis, the physical bounds that the functional modules of a moving cell experience in tissues may provide an overarching motif for novel approaches in diagnosis and therapy. [Preview Abstract] |
Tuesday, March 4, 2014 11:27AM - 11:39AM |
G10.00002: Role of mismatch in mechanical properties in cancer cell migration Julian Butcher, Moumita Das Recent experiments suggest that the mechanical stiffness of cells and their interaction with their surroundings undergo remarkable changes during tumor progression [1,2]. An intriguing experimental result in this area suggests that the mismatch in the elasticity and adhesive properties between cancer cells and cells that have not yet transformed may lead to enhanced cancer cell motility in a binary cell population [2]. Motivated by this, we study the mechanical response and dynamics of a binary system of active and deformable particles using Langevin Dynamics simulations. We characterize their motility by studying particle trajectories, mean square displacements and correlation functions. Our study may provide an understanding of the interplay of mechanical and statistical mechanical properties underlying the enhanced motility of cancer cells during metastasis [2]. \\[4pt] [1] S. Suresh, Biomechanics and biophysics of cancer cells, Acta Biomaterialia 3, 413 (2007).\\[0pt] [2] M. H. Lee, P. H. Wu, J. R. Staunton, R. Ros, G. D. Longmore, and D. Wirtz, Mismatch in Mechanical and Adhesive Properties Induces Pulsating Cancer Cell Migration in Epithelial Monolayer 102, 2731 (2012). [Preview Abstract] |
Tuesday, March 4, 2014 11:39AM - 11:51AM |
G10.00003: Quantifying Collective Cell Migration during Cancer Progression Rachel Lee, Christina Stuelten, Kerstin Nordstrom, Carole Parent, Wolfgang Losert As tumors become more malignant, cells invade the surrounding tissue and migrate throughout the body to form secondary, metastatic tumors. This metastatic process is initiated when cells leave the primary tumor, either individually or as groups of collectively migrating cells. The mechanisms regulating how groups of cells collectively migrate are not well characterized. Here we study the migration dynamics of epithelial sheets composed of many cells using quantitative image analysis techniques. By extracting motion information from time-lapse images of cell lines of varying malignancy, we are able to measure how migration dynamics change during cancer progression. We further investigate the role that cell-cell adhesion plays in these collective dynamics by analyzing the migration of cell lines with varying levels of E-cadherin (a cell-cell adhesion protein) expression. [Preview Abstract] |
Tuesday, March 4, 2014 11:51AM - 12:27PM |
G10.00004: Interplay of Genes and Mechanics in the Disorganization of Multicellular Structures Invited Speaker: Jan Liphardt As of last count, there are at least 10 risk factors for breast cancer. Some of these risk factors are genetic, such as mutations in the BRCA1 and 2 genes. Other risk factors are based on bulk tissue characteristics such as the degree to which the tissue attenuates x-rays (``mammographic density'') or its mechanical stiffness. Finally, risk and outcomes are also correlated with specific micro-anatomical features, such as collagen lines or tracts that extend radially outwards from the tumor-stromal interface. Despite significant progress in discovering risk factors, it is not understood if and how these risk factors interact. We have developed a simple model system for studying how genes, mechanics, and geometry interact to drive defined multi-cellular structures to an invasive phenotype. We have found that pairs or groups of Ras-transformed mammary acini with thinned basement membranes and weakened cell-cell junctions can generate collagen lines that then coordinate and accelerate transition to an invasive phenotype. When two or more acini mechanically interact by collagen lines, the pairs or groups of acini begin to disorganize rapidly and in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize slowly and to a lesser extent. When acini were mechanically isolated from other acini and also from the bulk gel by directed laser cutting of the collagen matrix, transition to an invasive phenotype was blocked in 20 of 20 experiments. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix and these directed mechanical interactions are necessary for rapid transition to an invasive phenotype. This new model system may help to understand the interplay of genes, mechanics, and geometry in transition to an invasive phenotype.\\[4pt] In collaboration with Quanming Shi, Rajarshi P. Ghosh, Hanna Engelke, Bay Area Physical Sciences Oncology Center and University of California, Berkeley; Chris H. Rycroft, Bay Area Physical Sciences Oncology Center, University of California, Berkeley, and Lawrence Berkeley National Laboratory; Luke Cassereau, Bay Area Physical Sciences Oncology Center and University of California, San Francisco; James A. Sethian, Bay Area Physical Sciences Oncology Center, University of California, Berkeley, and Lawrence Berkeley National Laboratory; and Valerie M. Weaver, Bay Area Physical Sciences Oncology Center and University of California, San Francisco. \\[4pt] Reference:\\[0pt] Rapid disorganization of mechanically interacting systems of mammary acini Q. Shi, RP. Ghosh, H. Engelke, CH. Rycroft, L. Cassereau, JA. Sethian, VM. Weaver, and J. Liphardt, PNAS 111(2), 658-663 (2014) [Preview Abstract] |
Tuesday, March 4, 2014 12:27PM - 12:39PM |
G10.00005: Emergence of therapy resistance in multiple myeloma in heterogeneous microenvironment Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Ariosto Silva, Robert Gatenby, Hyungsung Kim, Nader Pourmand, Robert Austin, James Sturm Cancer chemotherapy resistance is always a problem that is not clear considering spatial heterogeneity in the tumor microenvironment. We culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region in a microfluidic device which mimics the tumor microenvironment with a chemotherapy drug gradient and microhabitats. Resistance of the multiple myeloma cells to doxorubicin emerged within two weeks. For the resistant cells evolved from the devices, the doxorubicin concentration that inhibits 50\% of the controlled population increased by 16-fold than the parental cells. Whole transcriptome sequencing revealed that 39\% of newly acquired mutational hotspots (the genes with more than 3 non-synonymous point mutation) of the resistant cells are involved in apoptosis and DNA repair. On the other hand, 40\% of the non-mutated genes that are abnormally regulated in the resistant cells, are involved in metabolism, biosynthesis, and biomolecular transport. Among them, metabolic drug efflux pumps and oxidative stress scavengers are up-regulated to reduce the cytotoxicity of doxorubicin and further result in the resistance. The roles of the spatial drug gradients and microhabitats in rapid emergence of cancer resistance will be discussed. [Preview Abstract] |
Tuesday, March 4, 2014 12:39PM - 12:51PM |
G10.00006: Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions Gabor Balazsi, Eun-Jin Kim, Marsha Rosner The sources and consequences of nongenetic variability in metastatic progression are largely unknown. To address these questions, we characterize the transcriptional regulatory network around the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP). It was previously shown that RKIP negatively regulates the transcription factor BACH1, which promotes breast cancer metastasis. Here we demonstrate that BACH1 acts in a double negative (overall positive) feedback loop to inhibit RKIP transcription in breast cancer cells. BACH1 also negatively regulates its own transcription. Analysis of the RKIP-BACH1 network reveals the existence of an inverse relationship between BACH1 and RKIP involving both monostable and bistable transitions between ``low BACH1, high RKIP'' and ``high BACH1, low RKIP'' cellular states that can potentially give rise to nongenetic variability. Single cell analysis confirmed the antagonistic relationship between RKIP and BACH1, and showed cell line-dependent signatures consistent with bistable behavior. Together, our results suggest that the mutually repressive relationship between metastatic regulators such as RKIP and BACH1 can play a key role in determining metastatic progression in cancer. [Preview Abstract] |
Tuesday, March 4, 2014 12:51PM - 1:03PM |
G10.00007: Role of Fiber Length on Phagocytosis {\&} Inflammatory Response Leonid Turkevich, Carahline Stark, Julie Champion Asbestos fibers have long been associated with lung cancer death. The inability of immune cells (e.g. macrophages) to effectively remove asbestos leads to chronic inflammation and disease. This study examines the role of fiber length on toxicity at the cellular level using model glass fibers. A major challenge is obtaining single diameter fibers but differing in length. Samples of 1 micron diameter fibers with different length distributions were prepared: short fibers (less than 15 microns) by aggressive crushing, and long fibers (longer than 15 microns) by successive sedimentation. Time-lapse video microscopy monitored the interaction of MH-S murine alveolar macrophages with the fibers: short fibers were easily internalized by the macrophages, but long fibers resisted internalization over many hours. Production of TNF-$\alpha $ (tumor necrosis factor alpha), a general inflammatory secreted cytokine, and Cox-2 (cyclo-oxygenase-2), an enzyme that produces radicals, each exhibited a dose-dependence that was greater for long than for short fibers. These results corroborate the importance of fiber length in both physical and biochemical cell response and support epidemiological observations of higher toxicity for longer fibers. [Preview Abstract] |
Tuesday, March 4, 2014 1:03PM - 1:39PM |
G10.00008: The Genetic Origins of Cancer Invited Speaker: Jonathan Licht |
Tuesday, March 4, 2014 1:39PM - 1:51PM |
G10.00009: Optical Properties of Human Cancer and Normal Cells Christopher Sander, Nan Sun, Jeffrey Johnson, Sharon Stack, Carol Tanner, Steven Ruggiero We have investigated the optical properties of human oral and ovarian cancer and normal cells. Specifically, we have measured the absolute optical extinction for both whole cells and intra-cellular material in aqueous suspension. Measurements were conducted over a wavelength range of 250 to 1000nm with 1 nm resolution using Light Transmission Spectroscopy (LTS). This provides both the absolute extinction of materials under study and, with Mie inversion, the absolute number of particles of a given diameter as a function of diameter in the range of 1 to 3000 nm. Our preliminary studies show significant differences in both the extinction and particle size distributions associated with cancer versus normal cells, which appear to be correlated with differences in the particle size distribution in the range of $\sim$ 50 to 250 nm. [Preview Abstract] |
Tuesday, March 4, 2014 1:51PM - 2:03PM |
G10.00010: Reaction rate theory of radiation exposure:Effects of dose rate on mutation frequency Masako Bando, Issei Nakamura, Yuichiro Manabe We revisit the {\it linear no threshold} (LNT) hypothesis deduced from the prominent works done by H. J. Muller for the DNA mutation induced by the artificial radiation and by W. L. Russell and E. M. Kelly for that of mega-mouse experiments, developing a new kinetic reaction theory. While the existing theoretical models primarily rely on the dependence of the total dose $D$ on the mutation frequency, the key ingredient in our theory is the {\it dose rate} $d(t)$ that accounts for decrease in the mutation rate during the time course of the cellular reactions. The general form for the mutation frequency with the constant dose rate $d$ is simply expressed as, $\frac{d F_m (t)}{dt}= A - B F_m(t)$, with $A = a_0+a_1(d+d_{eff})$ and $B = b_0+b_1(d+d_{eff})$. We discuss the solution for a most likely case with $B > 0$; $F_m(t) = [\frac{A}{B}- F_m(0)] (1-e^{-Bt}) + F_m(0)$ with the control value $F_m(0)$. We show that all the data of mega-mouse experiments by Russel with different dose rates fall on the universal scaling function $\Phi(\tau) \equiv \frac{[F_m(\tau) - F_m(0)]}{[A/B - F_m(0)]} = 1 - \exp{(-\tau)}$ with scaled time $\tau = Bt$. The concept of such a scaling rule provides us with a strong tool to study different species in a unified manner. [Preview Abstract] |
Tuesday, March 4, 2014 2:03PM - 2:15PM |
G10.00011: Modelling Spread of Oncolytic Viruses in Heterogeneous Cell Populations Michael Ellis, Hana Dobrovolny One of the most promising areas in current cancer research and treatment is the use of viruses to attack cancer cells. A number of oncolytic viruses have been identified to date that possess the ability to destroy or neutralize cancer cells while inflicting minimal damage upon healthy cells. Formulation of predictive models that correctly describe the evolution of infected tumor systems is critical to the successful application of oncolytic virus therapy. A number of different models have been proposed for analysis of the oncolytic virus-infected tumor system, with approaches ranging from traditional coupled differential equations such as the Lotka-Volterra predator-prey models, to contemporary modeling frameworks based on neural networks and cellular automata. Existing models are focused on tumor cells and the effects of virus infection, and offer the potential for improvement by including effects upon normal cells. We have recently extended the traditional framework to a 2-cell model addressing the full cellular system including tumor cells, normal cells, and the impacts of viral infection upon both populations. Analysis of the new framework reveals complex interaction between the populations and potential inability to simultaneously eliminate the virus and tumor populations. [Preview Abstract] |
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