Bulletin of the American Physical Society
APS March Meeting 2020
Volume 65, Number 1
Monday–Friday, March 2–6, 2020; Denver, Colorado
Session A26: Mechanics of Cells and Tissues Across Scales IFocus
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Sponsoring Units: DBIO GSNP DSOFT DPOLY Chair: Kandice Tanner, National Institutes of Health - NIH Room: 403 |
Monday, March 2, 2020 8:00AM - 8:36AM |
A26.00001: The nematic feedback between cancer cells and the extracellular matrix Invited Speaker: Bo Sun The reciprocal mechanical interaction between cancer cells and their extracellular matrix (ECM) has been shown to paly important roles in tumor growth, survival and metastasis. Previous studies have primarily focused on the cell-induced stiffness change of the ECM, which is often characterized using bulk measurement. On the cellular scale, however, ECM produce anisotropic mechanical microenvironment to the cells. Cell generated forces align ECM fibers, and the aligned fiber direct cell polarization and migration through contact guidance. These interactions create a nematic feedback between cancer cells and their local ECM. In this talk I will first discuss quantitative measurements of cellular response to 3D contact guidance cues, which are inevitiblly noisy and spatially heterogeneous. I will then discuss how cell-induced ECM alignment can be controlled by tumor geometry, and regulate the long-term invasive potential of tumor cells. Together, these results highlight the rich biomechanical functions and powerful control mechanisms of the ematic feedback between cancer cells and extracellular matrix. |
Monday, March 2, 2020 8:36AM - 8:48AM |
A26.00002: Mechanical regulation of shape deformation by matrix viscoelasticity in breast tissues Alberto Elosegui-Artola, Anupam Gupta, L Mahadevan, David Mooney The shape change is one of the phenomena seen in cancerous tissue and the physical mechanism that allows this process to take place has not been clear. The synthetic extracellular matrix (ECM) are typically almost purely elastic. In contrast, the physiological ECM in various tissues, such as brain, liver, adipose tissue, and coagulated bone marrow, etc. are all viscoelastic. Most of the studies to date have focussed largely on elastic properties of ECM. Recently synthetic ECMs have been developed which closely mimic the natural viscoelastic ECMs. In this study, we are further looking into the role of such mechanical properties in inducing the malignant phenotype in normal mammary epithelium MCF10A cell line. Based on these experimental findings we have proposed a mathematical model to capture the qualitative results. This is the first mechanical model to capture this epithelial to mesenchymal transition by changing the viscoelastic properties of ECM. We observe that as you increase the fluidic nature of the ECM, the cell proliferation rate increases, loses its spherical shape, the interface becomes rough and for small viscosities leads to the formation of fingers. We show it in the model that this finger formation can be arrested either by increasing the viscosity or elasticity. |
Monday, March 2, 2020 8:48AM - 9:00AM |
A26.00003: Why do rigid tumors contain soft cancer cells? Thomas Fuhs, Franziska Wetzel, Anatol W Fritsch, Dapeng Bi, Roland Stange, Steve Pawlizak, Tobias Kiessling, Erik Morawetz, Steffen Grosser, Frank Sauer, Jürgen Lippoldt, Fred Renner, Sabrina Friebe, Mareike Zink, Lars-Christian Horn, Bahriye Aktas, Klaus Bendrat, Maja Oktay, Axel Niendorf, John S Condeelis, Michael Höckel, M Cristina Marchetti, M. Lisa Manning, Josef Alfons Kaes As early as 50 AD, the Roman medical encyclopaedist Celsus recognized that solid tumors are stiffer than surrounding tissue. However, cancer cell lines are softer, which facilitates invasion. This paradox raises several questions: Does softness emerge from adaptation to mechanical and chemical cues in the external microenvironment? Or are soft cells already present inside a rigid primary tumor? We investigate primary samples from patients with mammary and cervical carcinomas on multiple length scales from tissue level down to single cells. We show that primary tumors a highly heterogeneous in their mechanical properties on the tissue level as well as cells do exhibit a broad distribution of rigidities, with a higher fraction of softer and more elongated cells compared to normal tissue. Mechanical modelling based on patient data reveals that tumors remain solid containing a significant fraction of very soft cells. Moreover, it predicts that in such tissues, softer cells spontaneously self-organize into multicellular streams, which we observe experimentallz. |
Monday, March 2, 2020 9:00AM - 9:12AM |
A26.00004: A tug of war between cell-cell and cell-ECM interaction during tumor invasion Yu Ling Huang, Sumit K Dey, Carina Shiau, Cindy Wu, Yujie Ma, Jeffrey Segall, MingMing Wu Tumor invasion within the interstitial space is critically regulated by the force balance between the cell-cell and cell-ECM adhesion. In this talk, we will present a newly developed 3D tumor model in which tumor spheroids were embedded within collagen matrix, and tumor cell dynamics are subsequently imaged and analyzed. We varied cell-cell and cell-ECM adhesion by using three epithelial cell lines with increasing expression levels of E-cadherin (responsible for cell-cell adhesion) and decreasing expression of integrin (responsible for cell-ECM adhesion). Interestingly, our results demonstrated that the tumor cells at the peripheral of the tumor spheroid underwent a tug of war between the cell-ECM and the cell-cell adhesion. Integrin dependent cell-ECM adhesion promoted tumor invasion, while E-cadhesion mediated cell-cell adhesion inhibited tumor invasion. |
Monday, March 2, 2020 9:12AM - 9:24AM |
A26.00005: Understanding the crosstalk between mechanical and chemical guidance in 3D cell migration Pedram Esfahani, Christopher Eddy, Jihan Kim, Ryan Wong, Bo Sun Critical to many physiological and pathological processes, human cells exhibit motility responses to a variety of chemical and mechanical environmental factors. This includes both contact guidance, where cells migrate along the ECM fibers axes; and chemotaxis, in which cells move against the gradient of a chemoattractant. Both cases had been studied extensively. However, there are some synergestic effects that are not fully characterized in 3D cell migration . To reveal the combined effects of mechanical and chemical guidance, and their possible crosstalk, we develop a magneto-micro-fluidics device to individually control the chemoattractant gradient as well as contact guidance cues . To objectively characterize the cell migration and morphologies, we developed a deep learning based cell tracking method. This novel experimental platform enables us to observe how cells respond to chemotaxis and contact guidance cues in both parallel and perpendicular orientations with respect to each other, as well as in varying strengths. In our continuing work, we will develop a mathematical model to recapitulate our experimental observations and fully characterize the cell response to coupled chemical and mechanical cues. |
Monday, March 2, 2020 9:24AM - 10:00AM |
A26.00006: The role of tissue biophysics in organ selectivity in metastasis Invited Speaker: Kandice Tanner In the event of metastastic disease, emergence of a lesion can occur at varying intervals from diagnosis and in some cases following successful treatment of the primary tumor. Is there a difference in strategy to facilitate outgrowth? Why is there a difference in latency? Genetic factors that drive metastatic progression have been identified, such as those involved in cell adhesion, signaling, extravasation and metabolism. However, organ specific biophysical cues may be a potent contributor to the establishment of these secondary lesions. Here I discuss using optical tweezer based active microrheology to measure the mechanical cues that may influence disseminated tumor cells in different organ microenvironments. I further discuss in vitro and in vivo preclinical models such as 3D culture systems and zebrafish in efforts of understanding the role of the biophysical properties of the stromal architecture on the earliest stage of organ colonization. |
Monday, March 2, 2020 10:00AM - 10:12AM |
A26.00007: Distinct Roles of Tumor-Associated Mutations in Collective Cell Migration Rachel M. Lee, Michele I. Vitolo, Wolfgang Losert, Stuart S. Martin Recent evidence suggests that groups of cells are more likely to form clinically dangerous metastatic tumors, emphasizing the importance of understanding mechanisms underlying collective behavior. The emergent collective behavior of migrating cell sheets in vitro has been shown to be disrupted in tumorigenic cells but the connection between this behavior and in vivo tumorigenicity is unclear. Here we use particle image velocimetry to measure a multi-dimensional collective migration phenotype for genetically defined cell types that range in their in vivo behavior from non-tumorigenic to aggressively malignant. By using cells with controlled mutations, we show that Ras activation and PTEN deletion lead to opposing effects on collective migration, despite both mutations being frequently found in patient tumors. |
Monday, March 2, 2020 10:12AM - 10:24AM |
A26.00008: Precision of flow sensing by self-communicating cells Michael Vennettilli, Sean Fancher, Nicholas Hilgert, Andrew Mugler Metastatic cancer cells have been observed to detect the direction of lymphatic flow by “self-communication”: they secrete a chemical which, due to the flow, does not return to the cell surface isotropically. The secretion rate is low, meaning detection noise may play an important role, but the sensory precision of this mechanism has not been explored. Here we derive the precision of flow sensing for two ubiquitous mechanisms: absorption of the chemical and binding/unbinding to surface receptors. We find that the latter mechanism is significantly more precise due to the fact that absorption distorts the signal that the cell aims to detect. Comparing to experiments, our results suggest that the cancer cells operate remarkably close to the physical detection limit. Furthermore, we predict that they should bind the chemical reversibly, not absorb it, a prediction that is supported by endocytosis data for these cells. |
Monday, March 2, 2020 10:24AM - 10:36AM |
A26.00009: Classification of healthy and cancerous cells using optical rheology and machine learning Erik Morawetz, Dimitrij Tschodu, Josef Alfons Kaes The optical stretcher (OS) probes single suspended cells with forces around 100 pN. It has been shown, that in the physiological regime of the OS carcinoma cells tend to be softer than their healthy counterparts. Yet, a clear characterization based on rheological data could not be achieved, even though its correlation with cancerous traits is strongly suggested. |
Monday, March 2, 2020 10:36AM - 10:48AM |
A26.00010: Modeling biophysical tumor-stroma interactions in 3D co-cultures of pancreatic cancer cells and pancreatic stellate cells Eric Struth, Jonathan P Celli Mechanical interactions between tumor cells and stromal components impact cancer progression and therapeutic response. Tumors of the pancreas in particular are associated with stiff fibrous stroma impacting growth and drug delivery. Here we use time lapse imaging to study contractile force mediated by adhesions between pancreatic ductal adenocarcinoma (PDAC) cells and pancreatic stellate cells (PSCs), a fibroblastic stromal signaling partner, in 3D culture on laminin rich extracellular matrix (ECM). PDAC cells overlaid on ECM form compact multicellular 3D nodules. When PSCs are introduced there is a profound change in growth behavior culminating in the formation of large connected structures mediated by contractile force of activated PSCs. We analyze this behavior using particle image velocimetry, as well as analysis of nodule size distribution. We use immunofluorescence to characterize the E-cadherin/N-cadherin adhesion in these co-cultures and show that E-cadherin deficient PDAC cells are unable to form adhesions with stromal cells and exhibit decreased contractility as a result. Going forward, we are leveraging this system to model and study drug delivery through fibrotic PDAC stroma and evaluate stromal depletion therapies. |
Monday, March 2, 2020 10:48AM - 11:00AM |
A26.00011: 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. |
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