Bulletin of the American Physical Society
APS March Meeting 2019
Volume 64, Number 2
Monday–Friday, March 4–8, 2019; Boston, Massachusetts
Session K66: Physics of Cancer |
Hide Abstracts |
Sponsoring Units: DBIO Chair: Rachel Lee, University of Maryland, College Park Room: BCEC 261 |
Wednesday, March 6, 2019 8:00AM - 8:12AM |
K66.00001: Mathematical modeling studies on spatial profiles of cyotoxic T cells in solid tumors Xuefei Li, Tina Gruosso, Morag Park, Herbert Levine Infiltration of CD8+ T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including Triple Negative Breast Cancers (TNBC). However, the mechanisms underlying different infiltration-levels are largely unknown. Here, we have characterized the spatial profile of CD8+ T cells around tumor-cell clusters in TNBC. Combining mathematical modeling and data analysis, we propose that there exists a possible chemo-repellent inside tumor-cell clusters, which prevents CD8+ T cells from infiltrating into tumor-cell clusters. Furthermore, investigation into the properties of collagen fibers suggests that variations in desmoplastic elements does not limit infiltration of CD8+ T lymphocytes into tumor-cell clusters, which is consistent with the prediction of our mathematical modeling analysis whereby CD8+ T cells are predicted to infiltrate the fibrotic barrier. |
Wednesday, March 6, 2019 8:12AM - 8:24AM |
K66.00002: Tumor spheroids explode in the presence of interstitial flows revealed by a 3D microfluidic model Yu Ling Huang, Yujie Ma, Cindy Wu, Carina Shiau, Jeffrey Segall, MingMing Wu Interstitial flows are ubiquitous in maintaining tissue homeostasis in living systems, and are known to be elevated in malignant tumors. However, most current in vitro assays are carried out in static conditions and do not include fluid flows. In our work, we developed a microfluidic model to study tumor spheroid invasion through 3D collagen architecture under well controlled flows. We discovered that tumor spheroids explode in the presence of flow in contrast to no flow condition. Possible mechanisms underlying this explosion will be discussed in my talk. Our work highlights the importance of biophysical parameters in regulating tumor cell invasion. |
Wednesday, March 6, 2019 8:24AM - 8:36AM |
K66.00003: The Role of Cell Migration Guidance Cues in Emergent Collective Behavior Rachel Lee, Matt J. Hourwitz, Phillip Alvarez, Keyata N. Thompson, Michele I. Vitolo, John T Fourkas, Wolfgang Losert, Stuart S. Martin Studying the dynamics of collective systems can provide insight into how the motion of individual active agents can lead to unexpected emergent collective behavior. As tumors cells migrate to form metastases, a particularly lethal stage of cancer, the cells’ collective behavior is disrupted. Although current research largely focuses on individual cells, recent evidence shows that the most dangerous tumor cells retain the ability to move as collective strands or clusters that metastasize together. In this work, we use quantitative image analysis tools and live-cell imaging to investigate how guidance cues influence cells with different tumorigenicity, leading to distinct migration behavior. |
Wednesday, March 6, 2019 8:36AM - 8:48AM |
K66.00004: Breast cancer cell migration in the bone microenvironment Natasha Cowley, Rhoda Hawkins We are investigating how material confining a cell affects cell motility and behaviour. In particular we look at how rigidity and geometry play a role by investigating the mechanical response of materials with different rigidities to cell generated forces. We model a cell as a viscous droplet with an active contractile boundary analogous to the actin cortex. We use the immersed boundary method to simulate a cell interacting with deformable elastic walls of various geometries. We look at the specific case of breast cancer metastasis to the bone. |
Wednesday, March 6, 2019 8:48AM - 9:00AM |
K66.00005: Physics of Cancer Metastasis Sezin Galigolu, Ozge Akbulut, Roujin Ghaffari, Tayfun Ozcelik, Ozgur Sahin, Serim Ilday Metastasis is the cause of 90% of deaths related to the cancer. Cancer cells metastasize by entering the bloodstream, where they are dragged to distant parts of the body, and exiting the blood to colonize on another organ. Epithelial-Mesenchymal Transition (EMT) of cancer cells and vice versa (MET), have been proven to be the essential processes underlying metastasis through “static measurements” of biochemical cues. However, it has never been studied under dynamic conditions mimicking the actual physical environment: The blood vessel has an undulated, quasi-2D topology. Blood forms complex flows, e.g., laminar, turbulent, shear flows and their combinations inside this topology. In the bloodstream, the cancer cells are traveling along with many different cells and other entities, where they also face random obstacles. All of these factors are important for the successful completion of the metastasis process. Here, we show how epithelial, mesenchymal, drug-resistant breast cancer cells and healthy breast cells behave in such a dynamic, quasi-2D confined system under complex flows and when faced with random obstacles. We will test their adaptability under extreme physical conditions to conclude the physics of cancer metastasis. |
Wednesday, March 6, 2019 9:00AM - 9:12AM |
K66.00006: Shear stress increases acidic vesicles and proton pumps enhancing prostate cancer progression Zeina Khan, Fazle Hussain Cells in the tumor microenvironment are subjected to increased interstitial fluid pressure due to the angiogenic growth of new leaky blood vessels which triggers lymphangiogenic growth for drainage. This subjects tumor cells to shear stresses of approximately 0.01-0.1 dynes/cm2, two to three orders of magnitude smaller than wall shear stresses in blood vessels. While acidic membrane-bound vesicles, such as endosomes and lysosomes, and the V-ATPase proton pumps located on their membranes have been pursued as cancer markers, their role in cancer cell mechanotransduction and enhancing cancer aggressiveness is only recently emerging. We demonstrate that moderately metastatic prostate cancer cells respond to shear stress by increasing endosomes, lysosomes, and proton pumps, thereby activating both complexes of the mechanistic target of rapamycin pathway – mTORC1 and mTORC2 – controllers of autophagy, protein synthesis, glucose and lipid metabolism, and cell cytoskeletal changes. We will also report on shear stress-induced changes in migration and glucose metabolism, where increases accompany enhanced aggressiveness. |
Wednesday, March 6, 2019 9:12AM - 9:24AM |
K66.00007: Spatial heterogenity of the mechanics of solid tumors Thomas Fuhs, Erik W. Morawetz, Frank Sauer, Steffen Grosser, Josef A Käs In solid tumors tissue that is stiffer than healthy tissue is formed by cells that are softer than healthy cells. We try to address this contradiction by spatially resolved investigation of the mechanics of solid tumors tissues. We are able to measure the elasticity of slices of solid tumors on the millimeter scale with micrometer spatial resolution by AFM. This avoids measuring only heavily selected regions or only single cells extracted from dissected tissue. At the same time we are able to precisely align our AFM data with immunohistological stains. We can correlate the spatial heterogeneity of the elasticity maps with the distribution of cytokeratin. We complete these measurements with elasticity data on the whole tissue scale obtained by magnetic resonance elastography and single cell data from optical stretcher measurements. Each set of measurements is performed with tissue and from the same tumor, minimizing the error through biological variance within a dataset. Through the combination of the measurements we are able to bridge the scales from single cells to tissue level, to see how the individual cells contribute to the whole. |
Wednesday, March 6, 2019 9:24AM - 9:36AM |
K66.00008: Mechanical interactions in 3D tumor/fibroblast co-culture models of pancreatic cancer Eric Struth, Jonathan P Celli Studies have shown that mechanical interactions between tumor cells and stromal components in the tumor microenvironment impact disease progression and therapeutic response. Tumors of the pancreas are associated with an abundance of stiff fibrous stroma impacting growth and drug delivery. Here we use time lapse imaging to study physical interactions between pancreatic ductal adenocarcinoma (PDAC) cells and stromal fibroblasts grown in 3D culture on laminin rich extracellular matrix (ECM). PDAC cells overlaid on ECM form compact multicellular 3D nodules. When fibroblasts are introduced there is a profound change in growth behavior culminating in the formation of large connected structures. We describe quantitative analysis of this behavior using particle image velocimetry. We contrast stromal interactions of PANC1 PDAC cells and a previously established associated drug-resistant sub-line, showing that drug naïve co-cultures and drug resistant co-cultures are quantifiably different in both distribution of per-frame average magnitude over time, as well as final spatial distribution of spheroids in the co-cultures. Going forward, the methodology for cultivating fibrotic PDAC tumors in vitro may comprise a useful platform for screening drug delivery approaches for this lethal disease. |
Wednesday, March 6, 2019 9:36AM - 9:48AM |
K66.00009: Mathematical analysis of the life-span shortening in mice induced by radiation Takahiro Wada, Tetsuhiro Kinugawa, Yuichiro Manabe, Masako Bando At Institute for Environmental Sciences, Japan, they are conducting experiments to continuously irradiate mice with low dose-rate radiation. In one experiment, they sacrifice a certain number of mice every 100 days and count the number of cancers in the body. They found that, in the irradiated group, the occurrence of cancer happens earlier and the average number of cancer is larger.In the other experiment, they keep the mice until the natural death and they found that the life span is shortened with the increase in the dose rate. |
Wednesday, March 6, 2019 9:48AM - 10:00AM |
K66.00010: Multiscale simulation of Ras-Raf interaction Sumantra Sarkar, Angel E Garcia Cells use a limited number of mutually interacting protein-protein interaction networks, called cell-signalling network to communicate with each other. The protein components of these signalling networks have been identified and their individual functions understood. However, how they interact with each other to produce a functional cell-signalling network is relatively poorly understood. An important cell signalling network involved in the growth and proliferation of cells is the MAPK pathway, which is activated through the formation of phosphorylated Ras-Raf protein complex. The formation of this complex at biologically relevant concentrations span multiple timescales, rendering traditional theoretical and experimental tools inadequate to study this problem in its entirety. Using recently developed accelerated simulation techniques, we have been able to overcome this barrier and have studied Ras-Raf interaction in biologically relevant concentrations and timescales. In this talk, I shall present new aspects of Ras-Raf kinetics revealed through these simulations and discuss their potential biological implications. |
Wednesday, March 6, 2019 10:00AM - 10:12AM |
K66.00011: Structure guided development of anti-cancer flexible-heteroarotinoid compounds Donghua Zhou, Maryam Mashayekhi, Dipendra Bhandari, Gil Repa Flexible-heteroarotinoid compounds have been developed for their anticancer activities. The lead compound SHetA2 is able to inhibit growth of a variety of cancer cell lines and tumors in animal tests, without toxicity to normal tissues. The growth inhibition is about 84% for A2780 ovarian cancer cell cultures; the inhibition efficacy often decreases in real tissues. Therefore, it is desirable to improve efficacy and potency by designing better analogues. We identified the SHetA2 binding site on the receptor protein mortalin using NMR methods. SHetA2 disrupts the interaction of mortalin with other proteins that are upregulated in cancer cells but not in normal cells. Molecular modeling indicated that the binding strength of an analogue could be enhanced by increasing hydrophobicity of the chroman unit and substitution of a certain polar group. Five series of compounds were synthesized to validate the hypotheses. Several redesigned compounds did outperform the parent compound SHetA2, achieving inhibition efficacy of about 94% along with slightly better potency. |
Wednesday, March 6, 2019 10:12AM - 10:24AM |
K66.00012: Anti-cancer drug containing apolioprotein B lipoparticle reconstitution and tracking in living cell Wei-Ping Chang, Chung Ching Lin, Hsueh-Liang Chu, Po-Yen Lin, Yu-Chuan Liang, Caleb G. Chen, Chia-Ching Chang Radicicol (Rad), an Hsp 90 inhibitor, is an antitumor drug which loses its antitumor activity during delivery process, in vivo. By adding Rad in the reconstituting apolioprotein B (apoB) process, a Rad containing reconstituted apoB lipoparticle (rABL) complex (Rad@rABL) can be reconstituted and characterized by photonic spectroscopies, differential scanning calorimetry and super resolution imaging. Interestingly, the Rad@rABL single molecule can be tracked within the living cell. The drug delivery route to the mitochondria in the Hep G2 cell line can be monitored. Moreover, the anticancer efficacy of Rad can be enhanced. In summary, rABL is an excellent and native self-assembly drugs carrier and living cell tracking agent. |
Wednesday, March 6, 2019 10:24AM - 10:36AM |
K66.00013: Predicting patient outcomes (TNBC) based on positions of cancer islands and CD8+ T cells using machine learning approach Guangyuan Yu, XUEFEI LI, Herbert Levine The infiltrations of T are different in patients, which could be a tool for the prognosis. High CD8+ T cell counts (both overall and inside cancer-cell islands) is associated with better patient outcome. However, a cut-off of the T-cell count has to be selected manually to separate groups of patients. In this work, we propose a method to classify the small patch of triple-negative breast cancer (TNBC) tumor and use the overall percentage of “good” patches as a marker to predict the prognosis, which is an automatic method of prognosis and could also be used for other cancers. The result shows that the machine learns the importance of cell count and cell infiltration and use the combination as an indicator for prognosis. |
Wednesday, March 6, 2019 10:36AM - 10:48AM |
K66.00014: The physics of normal and impaired mitochondrial electron transfer Pavithi Weerasinghe, Martha Villagran, Aijun Zhang, Dale J Hamilton, Brian J Miles, Jarek Wosik, John H Miller The mitochondrial electron transport chain (ETC) produces most of our bodies’ energy in the form of ATP. Within the ETC, complex II, also known as succinate dehydrogenase (SDH), plays a unique role in that it converts succinate to fumarate as part of the Krebs cycle while simultaneously feeding energetic electrons to the ETC. The electrons travel along a chain of three Fe-S clusters in subunit B (SDHB) before entering the membranous domain containing a heme group and ubiquinone, which ultimately transports them to complex III. Some SDHB mutations in the form of amino acid replacements trigger aggressive growth of certain cancers, such as paraganglioma and pheochromocytoma. We will discuss our collaborative experimental and theoretical program, which includes measurements of human tissue and cell lines, and calculations of normal and mutated electron tunneling rates using Marcus theory. Our preliminary results suggest that some mutations disrupt SDHB electron pathways, causing many electrons to fail to reach their ubiquinone target and instead spill out to generate reactive oxygen species that increase tumorigenicity. |
Wednesday, March 6, 2019 10:48AM - 11:00AM |
K66.00015: Comparison of Subcellular Nanoparticle Size Distributions Across Cell Types with Light Transmission Spectroscopy Alison Deatsch, Patrick Sansone, Nan Sun, Carol E Tanner, Steven Thomas Ruggiero The cellular cytoplasm is a complex environment with a wide breadth of both size and concentration of particles, making a comprehensive survey of the subcellular structures interesting and difficult. Using LTS, we measure optical extinction spectra over a wavelength range of ~220-1000 nm, then apply Mie Theory to obtain particle size distributions (PSD). We present improvements to previous spinach cell PSDs, as well as those of new cell types and a comparison of healthy and cancer cells. With a combination of advanced filtration and quantitative LTS (a method of obtaining the concentration directly from the magnitude of the absorption peaks in the extinction spectra), we have improved the measurement of particles <100 nm, allowing the accurate assessment of PSDs over a wide size range: from ~5 nm to 3000nm. These PSDs reveal a power law dependence of particle concentration, N(D), with diameter, D, where N(D) α D-α across cell types. We discuss values obtained for α and an in-depth comparison to literature for studies of both isolated subcellular structures and PSDs of other natural systems. We discuss modeling the cell as a self-similar system of spheres on many size scales, with the goal to enrich our understanding of the fundamental nature of particle packing in the cytoplasm. |
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