Bulletin of the American Physical Society
APS March Meeting 2021
Volume 66, Number 1
Monday–Friday, March 15–19, 2021; Virtual; Time Zone: Central Daylight Time, USA
Session F12: Physics of CancerFocus Live
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Sponsoring Units: DBIO Chair: Bo Sun, Oregon State University; Robert Austin, Princeton University |
Tuesday, March 16, 2021 11:30AM - 11:42AM Live |
F12.00001: Diffusion Tensor Imaging (DTI) Based Drug Diffusion - Population Model in a
Solid Tumor erdi kara, Aminur Rahman, Eugenio Aulisa, Souparno Ghosh In this work, we study the effect of drug distribution on tumor cell death when the drug is internally injected in the |
Tuesday, March 16, 2021 11:42AM - 11:54AM Live |
F12.00002: Distinct Roles of Tumor-Associated Mutations in Collective Cell Migration Rachel Lee, Michele I. Vitolo, Wolfgang Losert, Stuart S. Martin Emergent collective behavior plays an important role during cancer progression. Multiple studies suggest that cell groups are more likely to form clinically dangerous metastatic tumors. Prior in vitro work has found disrupted collective behavior in tumorigenic cells, but the connection between this behavior and in vivo tumorigenicity is unclear. Here we measure a multidimensional migration phenotype for a genetically defined experimental model of breast cancer. Using cells with controlled mutations, we find that PTEN deletion enhances collective migration. We also find that Ras activation suppresses collective behavior, even when combined with PTEN deletion. Both PTEN deletion and Ras activation are frequently found in cancer patients and the opposing effects of these two mutations on emergent behavior could be exploited in the development of novel treatments for metastasis. Our multidimensional characterization of emergent collective behavior is based on label-free imaging and thus could be applied to patient tumor samples for clinical assessments of metastatic potential. |
Tuesday, March 16, 2021 11:54AM - 12:06PM Live |
F12.00003: Spatial Distribution of Immune Cells in Tumors Juliana Wortman, Ting-Fang He, Shawn Solomon, Robert Zhang, Anthony Rosario, Roger Wang, Travis Y. Tu, Daniel Schmolze, Yuan Yuan, Susan E. Yost, Xuefei Li, Herbert Levine, Gurinder Atwal, Peter P. Lee, Clare Yu The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We describe various techniques we have developed to explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. We apply our approach to immune cells in images of tumor tissue taken from (triple negative) breast cancer patients. We find that there is a distinct difference in the spatial distribution of immune cells between good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) and poor clinical outcome (recurrence within 3 years of diagnosis). |
Tuesday, March 16, 2021 12:06PM - 12:18PM Live |
F12.00004: EMT-induced cell mechanical changes enhance mitotic rounding strength Kamran Hosseini, Anna Taubenberger, Carsten Werner, Elisabeth Fischer-Friedrich To undergo mitosis successfully, most animal cells need to acquire a round shape to provide space for the mitotic spindle. This mitotic rounding relies on mechanical deformation of surrounding tissue and is driven by forces emanating from actomyosin contractility. Cancer cells are able to maintain successful mitosis in mechanically challenging environments such as the increasingly crowded environment of a growing tumor, thus, suggesting an enhanced ability of mitotic rounding in cancer. Here, we show that epithelial mesenchymal transition (EMT), a hallmark of cancer progression and metastasis, gives rise to cell-mechanical changes in breast epithelial cells. These changes are opposite in interphase and mitosis and correspond to an enhanced mitotic rounding strength. Furthermore, we show that cell-mechanical changes correlate with a strong EMT-induced change in the activity of Rho GTPases RhoA and Rac1. Accordingly, we find that Rac1 inhibition rescues the EMT-induced cortex-mechanical phenotype. Our findings hint at a new role of EMT in successful mitotic rounding and division in mechanically confined environments such as a growing tumor. |
Tuesday, March 16, 2021 12:18PM - 12:30PM Live |
F12.00005: Quantifying ECM micromechanical remodeling by an invading tumor Austin Naylor, David H McIntyre, Bo Sun Tumors are known to remodel the local extracellular matrix (ECM) in which they live. This remodeling causes the stiffness of the ECM to change, and is a major footprint in diagnosing tumors, specifically metastatic solid tumors such as breast or brain tumors. However, most studies up to date conduct bulk rheology or macroscopic rigidity experiments on the remodeled ECM. By using optical tweezers based assays, we are able to probe the local remodeling of the ECM and measure the local micromechanics as the tumor continuously expands and invades into the surrounding ECM. We find that the tumor can introduce strong mechanical anisotropy as well as stiffen the ECM. We find that these remodelings are spatially and temporally dependent on the tumor invasion dynamics. We hypothesize that the found remodelings are dominated by two factors, the volume preservation of cells and the traction force generated by cells. We also test our results by using different geometries of tumors. |
Tuesday, March 16, 2021 12:30PM - 12:42PM Live |
F12.00006: Mean-field interactions between living cells in linear and nonlinear elastic matrices Chaviva Sirote, Yair Shokef Living cells respond to mechanical changes in the matrix surrounding them by applying contractile forces that are in turn transmitted to distant cells. We calculate the mechanical work that each cell performs in order to deform the matrix, and study how that energy changes when a contracting cell is surrounded by other cells with similar properties and behavior. We consider two simple effective geometries for the spatial arrangement of cells, with spherical and with cylindrical symmetries, and model the presence of neighboring cells by imposing zero-displacement at some distance from the cell, which represents the surface of symmetry between neighboring cells. We analytically calculate the resulting interaction energy in linear elastic matrices, and study its dependence on the geometry, on the cell’s stiffness, and on the cell’s regulatory behavior. In nonlinear, strain stiffening matrices, we obtain numerical solutions and complement them by asymptotic analytical approximations. |
Tuesday, March 16, 2021 12:42PM - 12:54PM Live |
F12.00007: Spatial variation in cell volume within proliferating tumorigenic cell clusters is amplified by gap-junction-mediated ion flow Eoin McEvoy, Yulong Han, Ming Guo, Vivek b Shenoy Sustained proliferation is a significant driver of cancer progression. Cell-cycle advancement is coupled with cell size, but it remains unclear how multiple cells interact to control their volume in 3D clusters. In this work, we propose a mechano-osmotic model to investigate the evolution of volume dynamics within multicellular systems. Volume control depends on an interplay between multiple cellular constituents, including gap junctions, mechanosensitive ion channels, energy-consuming ion pumps, and the actomyosin cortex, that coordinate to manipulate cellular osmolarity. In connected cells, we show that mechanical loading leads to the emergence of osmotic pressure gradients between cells with consequent increases in cellular ion concentrations driving swelling. Extending our modeling framework to the analysis of a growing cluster, we identify how gap junctions can amplify spatial variations in cell volume and, further, describe how the process depends on proliferation-induced solid stress. Our model may provide new insight into the role of gap junctions in breast cancer progression. |
Tuesday, March 16, 2021 12:54PM - 1:30PM Live |
F12.00008: Mechanical adaptation of metastatic cancer cells during organ colonization in vivo Invited Speaker: Kandice Tanner Metastasis defines the spread of primary tumors to distant organs. The metastatic process is a complex process involving genomic, biochemical and mechanical perturbations. Interestingly, different types of primary cancers preferentially metastasize to specific distal organs (organotropism), which cannot be explained solely by circulatory dynamics. One idea is that successful outgrowth depends on the ability of cancer cells to tune their mechanical properties to match the local mechanical properties of the organ. Here, we aim to understand the biomechanical adaptation of cancer cells at the mesoscale in the later stage of metastasis and its role in organotropism in vivo. Specifically, this study aims to identify unique mechanical drivers of extravasation in the brain that could be targeted to inhibit brain metastasis in breast cancer patients. We measured the intracellular rheological properties of malignant cells in vitro using optical tweezer active microrheology in vivo using zebrafish as a model for cancer metastasis. We present that cancer cells conditioned in different stiffnesses in vitro and in distant organs in vivo show distinct mechanical properties that also differ from that of the parental cell line. We also determined that breast cancer and melanoma cells soften after extravasation into the brain parenchyma in comparison to pre-extravasation. However, cells stiffen at one day post extravasation in vivo to match that of the local microenvironment. During extravasation process, cancer cells become more liquid-like and semi-flexible. Future work will focus on genetic regulation of this mechanical adaptation. |
Tuesday, March 16, 2021 1:30PM - 1:42PM Live |
F12.00009: Topological signatures in regulatory network enable phenotypic heterogeneity in small cell lung cancer Lakshya Chauhan, Uday Ram, Kishore Hari, Mohit Kumar Jolly Phenotypic (non-genetic) heterogeneity has significant implications for the development and evolution of organs, organisms, and populations. Recent observations in multiple cancers have unraveled the role of phenotypic heterogeneity in driving metastasis and therapy recalcitrance. However, the origins of such phenotypic heterogeneity are poorly understood in most cancers. Here, we investigate a regulatory network underlying phenotypic heterogeneity in small cell lung cancer, a devastating disease with no molecular targeted therapy, and abysmal prognosis. Discrete and continuous dynamical simulations of this network reveal its multistable behavior that can explain the co-existence of four experimentally observed phenotypes. Analysis of the network topology uncovers that multistability emerges from two subgroups of nodes in the network that are mutually inhibitory across the subgroups but mutually activatory within subgroups. Deciphering these topological signatures in apparently complex cancer-related regulatory networks can unravel their underlying organizing principles and offer a minimalistic rational approach to characterize phenotypic heterogeneity in a tumor. |
Tuesday, March 16, 2021 1:42PM - 1:54PM Live |
F12.00010: Tumor spheroid chemotaxis in epidermal growth factor gradients revealed by a 3D microfluidic platform Young Joon Suh, Mrinal Pandey, Jeffrey Segall, MingMing Wu Epidermal growth factor (EGF), a potent cytokine, is known to promote tumor invasion both in vivo and in vitro. Previously, we observed that single breast tumor cells embedded within a 3D collagen matrix displayed enhanced motility but no discernable chemotaxis in the presence of EGF gradients using a microfluidic platform. Inspired by a recent theoretical development that clustered mammalian cells respond differently to chemical gradients than single cells, we studied tumor spheroid invasion within a 3D ECM in the presence of EGF gradients. We found that EGF gradients promoted tumor cells to detach from the spheroid core, and the position of the tumor spheroid core showed a mild chemotactic response towards the EGF gradients. In addition, tumor cells detached from the spheroids showed significant chemokinesis but no discernable chemotactic response towards the EGF gradients. This work demonstrated that a cluster of tumor cells respond differently than single tumor cells towards EGF gradients and highlighted the importance of a tumor spheroid platform for chemotaxis studies. |
Tuesday, March 16, 2021 1:54PM - 2:06PM Live |
F12.00011: Understanding the crosstalk between mechanical and chemical guidance in 3d cell migration Pedram Esfahani, Bo Sun Critical to many physiological and pathological processes, cells exhibit motility responses to both contact guidance and chemotaxis. Independently both cases had been studied extensively, however, some synergistic effects are not fully characterized. To quantitively analyze the strength of their crosstalks, we develop a u-fluidics device to control the strength of chemo- as well as mechno- cues by aligning ECM fibers. Also, to objectively characterize the cell migration, we developed a ML-based cell tracking method. This platform enabled us to observe how cells respond to chemo/mechano cues in three major categories. First, when mechano and chemo cues are perpendicular, we observed two types of behavior. About one-third of the cells following a strong chemotaxis effect through a hopping effect meaning cells hope from an ECM fiber to the neighboring one. The rest of the cells in this category strongly only follow the ECM fibers with about the same speed as the other ones. Second, the ECM fibers are parallel with the chemoattractant gradient vector. Under this condition, the overall migration speed is larger but the hopping effect is much weaker in comparison with the first category while the overall chemotaxis effect is the same. |
Tuesday, March 16, 2021 2:06PM - 2:18PM Live |
F12.00012: Collective T cell Migration within a 3D printed Immunotherapy Model Cameron Morley, Thomas Angelini Introducing tumor RNA to T cell populations primes the immune cells to identify elusive cancers. Despite the increasing efficacy of this immunotherapeutic approach in the mouse model, the underlying mechanisms behind the ability of T cells to identify and target tumors is still being investigated. In order to systematically study the interactions of these two cell populations, we employ a method of 3D bioprinting into a bed of jammed microgels where we have control over the spatial relationship between the two cell types. With this capability, we can identify key time and lengthscales at which the T cells identify the tumor presence and generate a collective immune response. Data on the temporal evolution of T cells targeting the tumor will be shown, in which biased motion toward the tumor correlates with a diffusion time for cytokines to leave the tumor and trigger T cell targeting. By varying this spatiotemporal relationship, we determine the diffusion coefficient of this cytokine signaling response, enabling better predictive models for this immunotherapy. Furthermore, we will show indirect identification of the cytokine source and gene expression changes within the tumor cell populations that highlight their attempts at immune evasion. |
Tuesday, March 16, 2021 2:18PM - 2:30PM Live |
F12.00013: Game Theory Cancer Models of Cancer Cell-Stromal Cell Dynamics using Interacting Particle Systems Yusha Y Sun, Yinan Zheng, Gonzalo Torga, Kenneth J. Pienta, Robert Austin We describe an evolutionary game theory model that has been used to predict the population dynamics of interacting cancer and stromal cells. We first consider the mean field case assuming homogeneous and non-discrete populations. Interacting Particle Systems (IPS) are then presented as a discrete and spatial alternative to the mean field approach. Finally, we discuss cases where IPS gives results different from the mean field approach. |
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