Bulletin of the American Physical Society
APS March Meeting 2016
Volume 61, Number 2
Monday–Friday, March 14–18, 2016; Baltimore, Maryland
Session B39: Physics of Cancer and Development IFocus
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Sponsoring Units: DBIO GSOFT Chair: Arpita Upadhyaya, University of Maryland Room: 342 |
Monday, March 14, 2016 11:15AM - 11:51AM |
B39.00001: Real-time Visualization of Tissue Dynamics during Embryonic Development and Malignant Transformation Invited Speaker: Kenneth Yamada Tissues undergo dramatic changes in organization during embryonic development, as well as during cancer progression and invasion. Recent advances in microscopy now allow us to visualize and track directly the dynamic movements of tissues, their constituent cells, and cellular substructures. This behavior can now be visualized not only in regular tissue culture on flat surfaces (`2D' environments), but also in a variety of 3D environments that may provide physiological cues relevant to understanding dynamics within living organisms. Acquisition of imaging data using various microscopy modalities will provide rich opportunities for determining the roles of physical factors and for computational modeling of complex processes in living tissues. Direct visualization of real-time motility is providing insight into biology spanning multiple spatio-temporal scales. Many cells in our body are known to be in contact with connective tissue and other forms of extracellular matrix. They do so through microscopic cellular adhesions that bind to matrix proteins. In particular, fluorescence microscopy has revealed that cells dynamically probe and bend the matrix at the sites of cell adhesions, and that 3D matrix architecture, stiffness, and elasticity can each regulate migration of the cells. Conversely, cells remodel their local matrix as organs form or tumors invade. Cancer cells can invade tissues using microscopic protrusions that degrade the surrounding matrix; in this case, the local matrix protein concentration is more important for inducing the micro-invasive protrusions than stiffness. On the length scales of tissues, transiently high rates of individual cell movement appear to help establish organ architecture. In fact, isolated cells can self-organize to form tissue structures. In all of these cases, in-depth real-time visualization will ultimately provide the extensive data needed for computer modeling and for testing hypotheses in which physical forces interact closely with cell signaling to form organs or promote tumor invasion. [Preview Abstract] |
Monday, March 14, 2016 11:51AM - 12:03PM |
B39.00002: Emergence of tissue mechanics from cellular processes: shaping a fly wing Matthias Merkel, Raphael Etournay, Marko Popovic, Amitabha Nandi, Holger Brandl, Guillaume Salbreux, Suzanne Eaton, Frank Jülicher Nowadays, biologistsare able to image biological tissueswith up to 10,000 cells in vivowhere the behavior of each individual cell can be followed in detail.However, how precisely large-scale tissue deformation and stresses emerge from cellular behavior remains elusive. Here, we study this question in the developing wing of the fruit fly. To this end, we first establish a geometrical framework that exactly decomposes tissue deformation into contributions by different kinds of cellular processes. These processes comprise cell shape changes, cell neighbor exchanges, cell divisions, and cell extrusions. As the key idea, we introduce a tiling of the cellular network into triangles. This approach also reveals that tissue deformation can also be created by correlated cellular motion. Based on quantifications using these concepts, we developed a novel continuum mechanical model for the fly wing. In particular, our model includes active anisotropic stresses and a delay in the response of cell rearrangements to material stresses. A different approach to study the emergence of tissue mechanics from cellular behavior are cell-based models. We characterize the properties of a cell-based model for 3D tissues that is a hybrid between single particle models and the so-called vertex models. [Preview Abstract] |
Monday, March 14, 2016 12:03PM - 12:15PM |
B39.00003: Quantifying the mechanics of embryonic tissues in vivo and in situ Otger Campas The sculpting of tissues and organs involves a tight spatiotemporal regulation of several physical fields, including active mechanical stresses and the local material properties. Despite the relevance of mechanics in embryonic morphogenesis, very little is known about the mechanisms by which tissue mechanics affects/controls developmental processes, mainly because it has not been possible to quantify mechanics within developing tissues in vivo and in situ. I will present two new techniques that permit direct quantification of (1) mechanical stresses at both tissue and cellular scales and (2) the material properties of the cellular microenvironment, in situ within living tissues and developing organs. Using these novel techniques, we characterize the mechanics of cell aggregates (in vitro), living mouse mandibles (ex vivo) and live zebrafish embryonic tissues (in vivo). [Preview Abstract] |
Monday, March 14, 2016 12:15PM - 12:27PM |
B39.00004: Cancer cell elasticity response to the mechanics of microenvironment Jingqiang Li, Raymond Fang, Kevin Jiang, Ian Lian, Ching-Hwa Kiang Cells can sense and response to the mechanical properties of their microenvironment. In particular, the rigidity of the cell's microenvrironment is regarded as a physical parameter of interest given its regulation of various cellular processes, including proliferation, differentiation and migration. Currently, in vitro cancer studies primarily performed by monolayer culture grown on the rigid polystyrene surfaces, but in vivo cancer cells interact with much softer tissue. Here, we utilize a new soft substrate cell culture platform to mimic tissues with various stiffness within the physiological range (0.2 – 100 kPa). We apply atomic force microscopy (AFM) to probe the elastic behaviors of three different cancer cell lines so as to emulate the essential features in the in vivo microenvironment. We observed that the substrate stiffness has a significant effect on the cell morphology and elasticity. The results of our study could have important implications regarding to the physics of cancer metastasis. [Preview Abstract] |
Monday, March 14, 2016 12:27PM - 12:39PM |
B39.00005: Cell Membrane Softening in Cancer Cells Sebastian Schmidt, Chris Händel, Josef Käs Biomechanical properties are useful characteristics and regulators of the cell's state. Current research connects mechanical properties of the cytoskeleton to many cellular processes but does not investigate the biomechanics of the plasma membrane. We evaluated thermal fluctuations of giant plasma membrane vesicles, directly derived from the plasma membranes of primary breast and cervical cells and observed a lowered rigidity in the plasma membrane of malignant cells compared to non-malignant cells. To investigate the specific role of membrane rigidity changes, we treated two cell lines with the Acetyl-CoA carboxylase inhibitor Soraphen A. It changed the lipidome of cells and drastically increased membrane stiffness by up regulating short chained membrane lipids. These altered cells had a decreased motility in Boyden chamber assays. Our results indicate that the thermal fluctuations of the membrane, which are much smaller than the fluctuations driven by the cytoskeleton, can be modulated by the cell and have an impact on adhesion and motility. [Preview Abstract] |
Monday, March 14, 2016 12:39PM - 12:51PM |
B39.00006: Network motifs that stabilize the hybrid epithelial/mesenchymal phenotype Mohit Kumar Jolly, Dongya Jia, Satyendra Tripathi, Samir Hanash, Sendurai Mani, Eshel Ben-Jacob, Herbert Levine Epithelial to Mesenchymal Transition (EMT) and its reverse -- MET -- are hallmarks of cancer metastasis. While transitioning between E and M phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) phenotype that enables collective cell migration as a cluster of Circulating Tumor Cells (CTCs). These clusters can form 50-times more tumors than individually migrating CTCs, underlining their importance in metastasis. However, this hybrid E/M phenotype has been hypothesized to be only a transient one that is attained en route EMT. Here, via mathematically modeling, we identify certain `phenotypic stability factors' that couple with the core three-way decision-making circuit (miR-200/ZEB) and can maintain or stabilize the hybrid E/M phenotype. Further, we show experimentally that this phenotype can be maintained stably at a single-cell level, and knockdown of these factors impairs collective cell migration. We also show that these factors enable the association of hybrid E/M with high stemness or tumor-initiating potential. Finally, based on these factors, we deduce specific network motifs that can maintain the E/M phenotype. Our framework can be used to elucidate the effect of other players in regulating cellular plasticity during metastasis. [Preview Abstract] |
Monday, March 14, 2016 12:51PM - 1:03PM |
B39.00007: Combinatorial Interventions Inhibit the Epithelial-to-Mesenchymal Transition and Support Hybrid Cellular Phenotypes Jorge G. T. Zanudo, S.N. Steinway, P.J. Michel, D.J. Feith, T.P. Loughran Jr., Reka Albert Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site and spread to other parts of the body. The molecular network regulating EMT involves the cooperation and cross-talk between multiple signaling pathways and key transcription factors, which we incorporated into systems-level logical network model for EMT. Using the EMT network model, we investigate potential EMT-suppressing interventions by identifying which individual and combinatorial perturbations suppress the induction of EMT by TGF$\beta $, an important signal driving EMT in liver cancer. We find that all non-trivial interventions are combinatorial and involve the inhibition of the SMAD complex together with other targets, several of which we experimentally tested and validated using liver cancer cell lines. We compare the combinatorial interventions with the results from a network control method we recently developed, which allowed us to determine the specific feedback regulatory motifs through which the interventions suppress EMT. Our results also reveal that blocking certain network components gives rise to steady states that are intermediate to the epithelial and mesenchymal states, supporting the existence of hybrid epithelial-mesenchymal states. [Preview Abstract] |
Monday, March 14, 2016 1:03PM - 1:15PM |
B39.00008: Testing the differential adhesion hypothesis across the epithelial-mesenchymal transition Steve Pawlizak, Anatol Fritsch, Steffen Grosser, Linda Oswald, Lisa Manning, Josef Kas We analyze the properties of three epithelial/mesenchymal cell lines that exhibit a shift in cadherin levels characteristic of an epithelial-mesenchymal transition (EMT) associated with processes such as metastasis, to quantify the role of cell cohesion in cell sorting and compartmentalization. We develop a unique set of methods to measure cell-cell adhesiveness, cell stiffness and cell shapes, and compare the results to predictions from cell sorting in mixtures of cell populations. We find that the final sorted state is extremely robust among all three cell lines independent of epithelial or mesenchymal state, suggesting that cell sorting may play an important role in organization and boundary formation in tumours. We find that surface densities of adhesive molecules do not correlate with measured cell-cell adhesion, but do correlate with cell shapes, cell stiffness and the rate at which cells sort, in accordance with an extended differential adhesion hypothesis (DAH). Surprisingly, the DAH does not correctly predict the final sorted state. This suggests that these tissues are not behaving as immiscible fluids, and that dynamical effects such as directional motility, friction and jamming may play an important role in tissue compartmentalization across the EMT. [Preview Abstract] |
Monday, March 14, 2016 1:15PM - 1:27PM |
B39.00009: Polymeric Nanocomposite that Mimics in vivo ECM Topography in Tissue using Magnetic Field-induced Particle Self-assembly. Jiyun Kim, Jack Staunton, Kandice Tanner 3D biomaterials that mimic a certain physical or chemical aspect of cellular environment have been used to recreate the diversity of the tissue microenvironment. Especially, physical characteristics of these materials such as topography, dimension and stiffness, have known to have crucial effects on cell fate and cell malignancy. Here, we propose a technique that is able to create diverse topographies in 3D polymeric scaffold for the purpose of mimicking the structural aspect of tissue microenvironment. To achieve this, we exploit the magnetic field-directed assembly of super paramagnetic particles to fabricate chain-distributed architecture such that we can study the effects of extracellular matrix (ECM) topography on cell behavior. First, we chemically cross-link proteins including fibronectin, laminin and bovine albumin serum on the surface of magnetic particles to make the building blocks for artificial topography. Then, we assemble these particles by applying the parallel magnetic field in a surrogate polymeric matrix and solidify the matrix to maintain the assembled topography. Using this simple technique, we patterned diverse topographies in 3D including globular, fibril or interfaced architectures without chafing other material characteristics of the scaffold matrix, such as stiffness and molecular diffusion. We demonstrated that the fibril architecture guilds the dendritic extension of fibroblasts and neuron-like cells, compared to the cells grown in the globular architecture lacking anisotropic guidance cues. [Preview Abstract] |
Monday, March 14, 2016 1:27PM - 1:39PM |
B39.00010: Interplay of differential cell mechanical properties, motility, and proliferation in emergent collective behavior of cell co-cultures Leo Sutter, Dan Kolbman, Mingming Wu, Minglin Ma, Moumita Das The biophysics of cell co-cultures, i.e. binary systems of cell populations, is of great interest in many biological processes including formation of embryos, and tumor progression. During these processes, different types of cells with different physical properties are mixed with each other, with important consequences for cell-cell interaction, aggregation, and migration. The role of the differences in their physical properties in their collective behavior remains poorly understood. Furthermore, until recently most theoretical studies of collective cell migration have focused on two dimensional systems. Under physiological conditions, however, cells often have to navigate three dimensional and confined micro-environments. We study a confined, three-dimensional binary system of interacting, active, and deformable particles with different physical properties such as deformability, motility, adhesion, and division rates using Langevin Dynamics simulations. Our findings may provide insights into how the differences in and interplay between cell mechanical properties, division, and motility influence emergent collective behavior such as cell aggregation and segregation experimentally observed in co-cultures of breast cancer cells and healthy breast epithelial cells. [Preview Abstract] |
Monday, March 14, 2016 1:39PM - 1:51PM |
B39.00011: How do heterogeneities in single cell rigidity influence the mechanical behavior at the tissue level? Dapeng Bi, Franziska Wetzel, Anatol Fritsch, M. Cristina Marchetti, M. Lisa Manning, Josef Kaes It has been long recognized that solid tumor tissues are mechanically more rigid than surrounding healthy tissues. However recent experiments have shown that in primary tumor samples from patients with mammary and cervix carcinomas, cells exhibit a broad distribution of rigidities, with a higher fraction of softer and more contractile cells compared to normal tissues. This gives rise to a paradox: does softness emerge from adaptation to mechanical and chemical cues in the external microenvironment, or are soft cells already present inside a primary solid tumor? Motivated by these observations, we study a model of dense tissues that incorporates the experimental data for cell stiffness variations to reveal that, surprisingly, tumors with a significant fraction of very soft cells can still remain rigid. Moreover, in tissues with the observed distributions of cell stiffnesses, softer cells spontaneously self-organize into lines or streams, possibly facilitating cancer metastasis. [Preview Abstract] |
Monday, March 14, 2016 1:51PM - 2:03PM |
B39.00012: Modeling the Spatiotemporal Evolution of the Melanoma Tumor Microenvironment Alexandra Signoriello, Marcus Bosenberg, Mark Shattuck, Corey O'Hern The tumor microenvironment, which includes tumor cells, tumor-associated macrophages (TAM), cancer-associated fibroblasts, and endothelial cells, drives the formation and progression of melanoma tumors. Using quantitative analysis of in vivo confocal images of melanoma tumors in three spatial dimensions, we examine the physical properties of the melanoma tumor microenvironment, including the numbers of different cells types, cell size, and morphology. We also compute the nearest neighbor statistics and measure intermediate range spatial correlations between different cell types. We also calculate the step size distribution, mean-square displacement, and non-Gaussian parameter from the spatial trajectories of different cell types in the tumor microenvironment. [Preview Abstract] |
Monday, March 14, 2016 2:03PM - 2:15PM |
B39.00013: Stochastic modeling and experimental analysis of phenotypic switching and survival of cancer cells under stress Seyed Alireza Zamani Dahaj, Niraj Kumar, Bala Sundaram, Jonathan Celli, Rahul Kulkarni The phenotypic heterogeneity of cancer cells is critical to their survival under stress. A significant contribution to heterogeneity of cancer calls derives from the epithelial–mesenchymal transition (EMT), a conserved cellular program that is crucial for embryonic development. Several studies have investigated the role of EMT in growth of early stage tumors into invasive malignancies. Also, EMT has been closely associated with the acquisition of chemoresistance properties in cancer cells. Motivated by these studies, we analyze multi-phenotype stochastic models of the evolution of cancers cell populations under stress. We derive analytical results for time-dependent probability distributions that provide insights into the competing rates underlying phenotypic switching (e.g. during EMT) and the corresponding survival of cancer cells. Experimentally, we evaluate these model-based predictions by imaging human pancreatic cancer cell lines grown with and without cytotoxic agents and measure growth kinetics, survival, morphological changes and (terminal evaluation of) biomarkers with associated epithelial and mesenchymal phenotypes. The results derived suggest approaches for distinguishing between adaptation and selection scenarios for survival in the presence of external stresses. [Preview Abstract] |
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