Bulletin of the American Physical Society
APS March Meeting 2016
Volume 61, Number 2
Monday–Friday, March 14–18, 2016; Baltimore, Maryland
Session C39: Physics of Cancer and Development IIFocus
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Sponsoring Units: DBIO GSOFT Chair: Kandice Tanner, National Institute of Health Room: 342 |
Monday, March 14, 2016 2:30PM - 2:42PM |
C39.00001: Stabilization of EphA2 dimers as a novel anti-cancer strategy Deo Singh, Fozia Ahmed, Matt Salloto, Kalina Hristova We have recently shown that EphA2 receptors exist in a monomer-dimer equilibrium in the absence of ligand. The monomers promote tumorigenic activity and thus a therapeutic strategy that minimizes the monomer population may be beneficial in the clinic. The YSA peptide is an EphA2-targeting peptide that effectively delivers anticancer agents to cancer tumors. The quantitative measurements of the dimerization of EphA2 receptors in the presence of these peptides using quantitative spectral Forster resonance transfer (QS-FRET) methodology in conjunction with two-photon microscopy that has been developed recently in our lab suggests that this peptide stabilizes the EphA2 dimers. Thus, such peptides that stabilize the EphA2 dimers may be used for the treatment of some cancers that overexpress EphA2. [Preview Abstract] |
Monday, March 14, 2016 2:42PM - 2:54PM |
C39.00002: Criticality and Cancer Dormancy Amy Wu, David Liao, Vladimir Kirlin, Corina Tamita, Simon Levin, James Sturm, Robert Austin The presence of driver mutations and subsequent clonal expansion by Darwinian evolution does not explain dormancy and re-emergence of cancer from a community of cancer and stromal cells. Dormancy appears to be a collective property of multiple cell communities including non-cancerous cells. At the simplest level, we view cancer cells interacting with stromal cells via complex, non-linear population dynamics, dynamics which can lead to very non-intuitive but perhaps deterministic and understandable progression dynamics of cancer. We explore here the dynamics of stromal-cancer cell populations in the presence of a chemotherapy drug gradient to determine to what extent the time-dependence of the populations can be quantitively understood in spite of the underlying complexity of the individual agents. The surprising result is that a basic understanding, in a quantitive and predictive manner, can be achieved. It will be intriguing to move to predictive drug dosages, the population dynamics presented here provide a model system for the clinic. [Preview Abstract] |
Monday, March 14, 2016 2:54PM - 3:06PM |
C39.00003: ABSTRACT WITHDRAWN |
Monday, March 14, 2016 3:06PM - 3:18PM |
C39.00004: Development as a Factor in the Evolution of Modularity in Biological Systems Jessica Lowell Biological networks and other systems tend to be modular in structure, with reuse of motifs and the ability to be separated into semi-independent units. The evolutionary forces that produce this modularity are a topic of active research, as modular solutions rarely emerge from models of biological evolution. Through simulations combining evolution and development, I investigate the role that development plays in the emergence of modularity, using a popular metric for network modularity and representing non-network structures as networks in which building blocks are nodes and connections between them are arcs. Preliminary results show that the modularities of structures evolved by an L-systems-based evolutionary developmental algorithm are higher than those evolved by a non-developmental evolutionary algorithm that models evolution in the same way. To ensure that these results are not specific to a single algorithm, I am conducting evolutionary developmental simulations using other methods for simulating development, evolving both networks and building-block structures. This study sheds light on the role of development as a factor in the origin of modularity in biological networks and other biological systems. [Preview Abstract] |
Monday, March 14, 2016 3:18PM - 3:30PM |
C39.00005: Mechanoregulatory tumor-stroma crosstalk in pancreatic cancer: Measurements of the effects of extracellular matrix mechanics on tumor growth behavior, and vice-versa, to inform therapeutics Jonathan Celli, Dustin Jones, Hamid El-Hamidi, Gwendolyn Cramer, William Hanna, Andrew Caide, Seyedehrojin Jafari The rheological properties of the extracellular matrix (ECM) have been shown to play key roles in regulating tumor growth behavior through mechanotranduction pathways. The role of the mechanical microenvironment may be particularly important tumors of the pancreas, noted for an abundance of rigid fibrotic stroma, implicated in therapeutic resistance. At the same time, cancer cells and their stromal partners (e.g. tumor associated fibroblasts) continually alter the mechanical microenvironment in response to extracellular physical and biochemical cues as part of a two-way mechanoregulatory dialog. Here, we describe experimental studies using 3D pancreatic cell cultures with customized mechanical properties, combined with optical microrheology to provide insight into tumor-driven matrix remodeling. Quantitative microscopy provides measurements of phenotypic changes accompanying systematic variation of ECM composition in collagen and laminin-rich basement membrane admixtures, while analysis of the trajectories of passive tracer particles embedded in ECM report dynamic changes in heterogeneity, microstructure and local shear modulus accompanying both ECM stiffening (fibrosis) processes, and ECM degradation near invading cells. [Preview Abstract] |
Monday, March 14, 2016 3:30PM - 3:42PM |
C39.00006: Exploring Kupffer's Vescicle Through Self Propelled Particle Simulations Kassidy Lundy, Agnik Dasgupta, Jeff Amack, M. Lisa Manning Early development is an important stage in the formation of functional, relatively healthy organisms. In zebrafish embryos, a transient organ in the tailbud called Kupffer's Vescicle (KV) is responsible for the initial left-right (L-R) asymmetry that results in asymmetric organ and tissue placement in the adult zebrafish. Originating as a collection of symmetrically organized monociliated cells, the KV experiences a shift in cell shapes over time that leaves more cells on the anterior or top side of the KV. This arrangement helps to generate a stronger counter-clockwise fluid flow across the anterior side of the organ, which is required for L-R asymmetry. In seeking to understand the source of the shape changes occurring within the KV, we simulate a Self Propelled Particle (SPP) model that includes parameters for cell polarization and speed. We model the KV as a large particle moving in a straight line with constant velocity to mimic the physical forces of the notochord acting on this organ, and we model the surrounding tailbud cells as smaller, slower active particles with an orientation that changes over time due to rotational noise. Our goal is to calculate the forces exerted on the KV by the surrounding tissue, to see if they are sufficient to explain the shape changes we observe in the KV that lead to L-R asymmetry. [Preview Abstract] |
Monday, March 14, 2016 3:42PM - 4:18PM |
C39.00007: Systems-level analysis of the regulation and function of p53 dynamics in cancer. Invited Speaker: Eric Batchelor Living cells use complex signaling pathways to detect environmental stimuli and generate appropriate responses. As methods for quantifying intracellular signaling have improved, several signaling pathways have been found to transmit information using signals that pulse in time. The transcription factor p53 is a key tumor suppressor and stress-response regulator that exhibits pulsatile dynamics. In response to DNA double-strand breaks, the concentration of p53 in the cell nucleus increases in pulses with a fixed amplitude, duration, and period; the mean number of pulses increases with DNA damage. p53 regulates the expression of over 100 target genes involved in a range of cellular stress responses including apoptosis, cell cycle arrest, and changes in metabolism. p53 pulsing directly impacts p53 function: altering p53 dynamics by pharmacologically inhibiting p53 degradation changes patterns of target gene expression and cell fate. While p53 pulsing serves an important signaling function, it is less clear what it accomplishes mechanistically. Here we will describe our recent efforts to determine the impact of p53 pulsing on the dynamics and coordination of target gene expression. [Preview Abstract] |
Monday, March 14, 2016 4:18PM - 4:30PM |
C39.00008: Cell-Substrate Adhesion by Amoeboid Cells Bret Flanders, Krishna Panta Amoeboid migration is a rapid (10 $\mu $m min$^{-1})$ mode of migration that some tumor cells exhibit. To permit such rapid movement, the adhesive contacts between the cell and the substrate must be relatively short-lived and weak. In this study, we investigate the basic adhesive character of amoeboid cells (D. discoideum) in contact with silanized glass substrates. We observe the initiation and spreading of the adhesive contacts that these cells establish as they settle under gravity onto the substrate and relax towards mechanical equilibrium. The use of interference reflection microscopy and cellular tethering measurements have allowed us to determine the basic adhesive properties of the cell: the membrane-medium interfacial energy; the bending modulus; the equilibrium contact angle; and the work of adhesion. We find the time scale on which settling occurs to be longer than expected. Implications of these results on adhesion and migration will be discussed. [Preview Abstract] |
Monday, March 14, 2016 4:30PM - 4:42PM |
C39.00009: Fragmentation of cancer cells SIVA VANAPALLI, Nabiollah Kamyabi Tumor cells have to travel through blood capillaries to be able to metastasize and colonize in distant organs. Among the numerous cells that are shed by the primary tumor, very few survive in circulation. In vivo studies have shown that tumor cells can undergo breakup at microcapillary junctions affecting their survival. It is currently unclear what hydrodynamic and biomechanical factors contribute to fragmentation and moreover how different are the breakup dynamics of highly and weakly metastatic cells. In this study, we use microfluidics to investigate flow-induced breakup of prostate and breast cancer cells. We observe several different modes of breakup of cancer cells, which have striking similarities with breakup of viscous drops. We quantify the breakup time and find that highly metastatic cancer cells take longer to breakup than lowly metastatic cells suggesting that tumor cells may dynamically modify their deformability to avoid fragmentation. We also identify the role that cytoskeleton and membrane plays in the breakup process. Our study highlights the important role that tumor cell fragmentation plays in cancer metastasis. [Preview Abstract] |
Monday, March 14, 2016 4:42PM - 4:54PM |
C39.00010: Blood based cell biopsy for early detection of cancer Cha-Mei Tang, Daniel Adams, Diane Adams, R. Katherine Alpaugh, Massimo Cristofanilli, Stuart Martin, Saranya Chumsri, Jeffrey Marks Early detection (ED) of cancer holds the promise for less aggressive treatments and better outcome. However, there are few accepted methods for ED. We report on a previously unknown blood cell found specifically in the peripheral blood of many solid tumors. They are defined as Cancer Associated Macrophage-Like cells (CAMLs) and are characterized by large size (25-300$\mu$m) and expression of cancer markers. CAMLs were isolated on precision filters during blood filtration. We conducted prospective studies in breast cancer (BC) to ascertain CAML prevalence, specificity and sensitivity in relation to disease status at clinical presentation. We report on two related but separate studies: 1) the isolation of CAMLs from patients with known invasive BC, compared to healthy volunteers and, 2) a double blind study conducted on women undergoing core needle biopsy to evaluate suspicious breast masses. The studies show that CAMLs are found in all stages of BC and suggest that detection of CAMLs can differentiate patients with BC from those with benign breast conditions and healthy individuals. This non-invasive blood test can be potentially used for ED of BC and other malignancies after validation studies with the advantage of a minimally invasive procedure and longitudinal monitoring. [Preview Abstract] |
Monday, March 14, 2016 4:54PM - 5:06PM |
C39.00011: Quantifying Microtentacle Dynamics for Non-adherent Tumor Cells Eleanor Ory, Desu Chen, Kristi Chakrabarti, Stuart Martin, Wolfgang Losert In current cancer medicine, metastasis is still responsible for 90% of fatalities of cancer patients. Disseminated tumor cells reattaching to the blood vessel walls remains a critical and incompletely understood step in metastasis. One of the possible mechanisms for reattachment involves tubulin-based protrusions called microtentacles. It has been hypothesized that microtentacles form due to an imbalance between microtubules and actin cortex mechanical interactions. Using image analysis techniques on non-adherent breast tumor cells tethered to a surface under drug perturbations targeting microtubule stability, we are able to examine into microtentacle dynamics. We show that stabilizing tubulin leads to a greater number and length of microtentacles. [Preview Abstract] |
Monday, March 14, 2016 5:06PM - 5:18PM |
C39.00012: Electron holes appear to trigger cancer-implicated mutations. John Miller, Martha Villagran Malignant tumors are caused by mutations, which also affect their subsequent growth and evolution. We use a novel approach, computational DNA hole spectroscopy [M.Y. Suarez-Villagran {\&} J.H. Miller, \textit{Sci. Rep}. \textbf{5}, 13571 (2015)], to compute spectra of enhanced hole probability based on actual sequence data. A hole is a mobile site of positive charge created when an electron is removed, for example by radiation or contact with a mutagenic agent. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of reveal a correlation between hole spectrum peaks and spikes in human mutation frequencies. Importantly, we also find that hole peak positions that do~\textit{not} coincide with large variant frequencies often coincide with cancer-implicated mutations and/or (for coding DNA) encoded conserved amino acids. This enables combining hole spectra with variant data to identify critical base pairs and potential cancer `driver' mutations. Such integration of DNA hole and variance spectra could also prove invaluable for pinpointing critical regions, and sites of driver mutations, in the vast non-protein-coding genome. [Preview Abstract] |
Monday, March 14, 2016 5:18PM - 5:30PM |
C39.00013: Tumorigenesis and Greenhouse-Effect System Dynamics: Phenomenally Diverse, but Noumenally Similar? Sai Prakash We present a physicochemical model of tumorigenesis leading to cancer invasion and metastasis. The continuum-theoretic model, congruent with recent experiments, analyzes the plausibility of oncogenic neoplasia-induced cavitation or tensile yielding (plasticity) of the tumoral basement membrane (BM) to activate stromal invasion. The model abstracts a spheroid of normal and cancer cells that grows radially via water and nutrient influx while constrained by a stiffer BM and cell adhesion molecules. It is based on coupled fluid-solid mechanics and ATP-fueled mechano-damped cell kinetics, and uses empirical data alone as parameters. The model predicts the dynamic force and exergy (ATP) fields, and tumor size among other variables, and generates the sigmoidal dynamics of far-from-equilibrium biota. Simulations show that the tumor-membrane system, on neoplastic perturbation, evolves from one homeostatic steady state to another over time. Integrated with system dynamics theory, the model renders a key, emergent tissue-level feedback control perspective of malignancy: neoplastic tumors coupled with pathologically-softened BMs appear to participate in altered autoregulatory behavior, and likely undergo BM cavitation and stress-localized ruptures to their adhesome, with or without invadopoiesis, thereby, initiating invasion. Serendipitously, the results also reveal a noumenal similarity of the tumor-membrane to the earth-atmosphere open reactive system as concerns self-regulation. [Preview Abstract] |
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