Publications

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64 Publications visible to you, out of a total of 64
Impact of Fibrinogen, Fibrin Thrombi, and Thrombin on Cancer Cell Extravasation Using In Vitro Microvascular Networks.

Abstract (Expand)

A bidirectional association exists between metastatic dissemination and the hypercoagulable state associated with many types of cancer. As such, clinical studies have provided evidence that markers … associated with elevated levels of coagulation and fibrinolysis correlate with decreased patient survival. However, elucidating the mechanisms underpinning the effects of different components of the coagulation system on metastasis formation is challenging both in animal models and 2D models lacking the complex cellular interactions necessary to model both thrombosis and metastasis. Here, an in vitro, 3D, microvascular model for observing the formation of fibrin thrombi is described, which is in turn used to study how different aspects of the hypercoagulable state associated with cancer affect the endothelium. Using this platform, cancer cells expressing ICAM-1 are shown to form a fibrinogen-dependent bridge and transmigrate through the endothelium more effectively. Cancer cells are also demonstrated to interact with fibrin thrombi, using them to adhere, spread, and enhance their extravasation efficiency. Finally, thrombin is also shown to enhance cancer cell extravasation. This system presents a physiologically relevant model of fibrin clot formation in the human microvasculature, enabling in-depth investigation of the cellular interactions between cancer cells and the coagulation system affecting cancer cell extravasation.

Authors: E. Angelidakis, S. Chen, S. Zhang, Z. Wan, R. D. Kamm, S. E. Shelton

Date Published: 28th Jul 2023

Publication Type: Journal Article

Chemo-mechanical diffusion waves explain collective dynamics of immune cell podosomes.

Abstract (Expand)

Immune cells, such as macrophages and dendritic cells, can utilize podosomes, mechanosensitive actin-rich protrusions, to generate forces, migrate, and patrol for foreign antigens. Individual podosomes … probe their microenvironment through periodic protrusion and retraction cycles (height oscillations), while oscillations of multiple podosomes in a cluster are coordinated in a wave-like fashion. However, the mechanisms governing both the individual oscillations and the collective wave-like dynamics remain unclear. Here, by integrating actin polymerization, myosin contractility, actin diffusion, and mechanosensitive signaling, we develop a chemo-mechanical model for podosome dynamics in clusters. Our model reveals that podosomes show oscillatory growth when actin polymerization-driven protrusion and signaling-associated myosin contraction occur at similar rates, while the diffusion of actin monomers drives wave-like coordination of podosome oscillations. Our theoretical predictions are validated by different pharmacological treatments and the impact of microenvironment stiffness on chemo-mechanical waves. Our proposed framework can shed light on the role of podosomes in immune cell mechanosensing within the context of wound healing and cancer immunotherapy.

Authors: Z. Gong, K. van den Dries, R. A. Migueles-Ramirez, P. W. Wiseman, A. Cambi, V. B. Shenoy

Date Published: 22nd May 2023

Publication Type: Journal Article

Impact of Fibrinogen, Fibrin Thrombi, and Thrombin on Cancer Cell Extravasation Using In Vitro Microvascular Networks

Abstract

Not specified

Authors: Emmanouil Angelidakis, Sophia Chen, Shun Zhang, Zhengpeng Wan, Roger D. Kamm, Sarah E. Shelton

Date Published: 1st May 2023

Publication Type: Journal Article

Chemo-mechanical diffusion waves explain collective dynamics of immune cell podosomes

Abstract

Not specified

Authors: Ze Gong, Koen van den Dries, Rodrigo A. Migueles-Ramírez, Paul W. Wiseman, Alessandra Cambi, Vivek B. Shenoy

Date Published: 1st May 2023

Publication Type: Journal Article

Molecular origins of mutational spectra produced by the environmental carcinogen N-nitrosodimethylamine and S(N)1 chemotherapeutic agents.

Abstract (Expand)

DNA-methylating environmental carcinogens such as N-nitrosodimethylamine (NDMA) and certain alkylators used in chemotherapy form O (6)-methylguanine (m6G) as a functionally critical intermediate. NDMA … is a multi-organ carcinogen found in contaminated water, polluted air, preserved foods, tobacco products, and many pharmaceuticals. Only ten weeks after exposure to NDMA, neonatally-treated mice experienced elevated mutation frequencies in liver, lung and kidney of approximately 35-fold, 4-fold and 2-fold, respectively. High-resolution mutational spectra (HRMS) of liver and lung revealed distinctive patterns dominated by GC-->AT mutations in 5'-Pu-G-3' contexts, very similar to human COSMIC mutational signature SBS11. Commonly associated with alkylation damage, SBS11 appears in cancers treated with the DNA alkylator temozolomide (TMZ). When cells derived from the mice were treated with TMZ, N-methyl-N-nitrosourea, and streptozotocin (two other therapeutic methylating agents), all displayed NDMA-like HRMS, indicating mechanistically convergent mutational processes. The role of m6G in shaping the mutational spectrum of NDMA was probed by removing MGMT, the main cellular defense against m6G. MGMT-deficient mice displayed a strikingly enhanced mutant frequency, but identical HRMS, indicating that the mutational properties of these alkylators is likely owed to sequence-specific DNA binding. In sum, the HRMS of m6G-forming agents constitute an early-onset biomarker of exposure to DNA methylating carcinogens and drugs.

Authors: A. L. Armijo, P. Thongararm, B. I. Fedeles, J. Yau, J. E. Kay, J. J. Corrigan, M. Chancharoen, S. Chawanthayatham, L. D. Samson, S. E. Carrasco, B. P. Engelward, J. G. Fox, R. G. Croy, J. M. Essigmann

Date Published: 31st Mar 2023

Publication Type: Journal Article

Interaction of N-nitrosamines with binuclear copper complexes for luminescent detection.

Abstract (Expand)

Cu(I) from tetrakis(acetonitrile)copper(I) hexafluorophosphate ([Cu(MeCN)(4)]PF(6)) was complexed with five structurally related phosphines containing N-heterocycles. The interactions between the … resulting complexes and some N-nitrosamines were studied using X-ray crystallography as well as emission spectroscopy. Upon complexation, three phosphine ligands bridge two Cu(I) centers to give paddlewheel type structures that displayed a range of emission wavelengths spanning the visible region. N-Nitrosodimethylamine (NDMA) was shown to coordinate to one of the two copper centers in some of the paddlewheel complexes in the solid state and this interaction also quenches their emissions in solution. The influence of the weakly coordinating anion on crystal and spectroscopic properties of one of the paddlewheel complexes was also examined using tetrakis(acetonitrile)copper(I) perchlorate ([Cu(MeCN)(4)]ClO(4)) as an alternative Cu(I) source. Similarly, copper(II) perchlorate hexahydrate (Cu(ClO(4))(2).6H(2)O) was used for complexation to observe the impact of metal oxidation state on the two aforementioned properties. Lastly, the spectroscopic properties of the complex between Ph(2)P(1-Isoquinoline) and Cu(I) was shown to exhibit solvent dependence when the counterion is ClO(4)(-). These Cu(I) complexes are bench stable solids and may be useful materials for developing a fluorescence based detection method for N-nitrosamines.

Authors: H. Feng, S. L. Luo, R. G. Croy, J. M. Essigmann, T. M. Swager

Date Published: 7th Mar 2023

Publication Type: Journal Article

Benthic Fluxes of Fluorescent Dissolved Organic Material, Salt, and Heat Measured by Multiple-Sensor Aquatic Eddy Covariance.

Abstract (Expand)

Aquatic eddy covariance (AEC) is an in situ technique for measuring fluxes in marine and freshwater systems that is based on the covariance of velocity and concentration measurements. To date, AEC has … mainly been applied to the measurement of benthic oxygen fluxes. Here, development of a fast multiple-channel sensor enables the use of AEC for measurement of benthic fluxes of fluorescent material, salt, and heat at three distinct sites in Massachusetts, USA, including the Connecticut River, the Concord River, and Upper Mystic Lake. Benthic fluxes of salt, useful as a tracer for groundwater input (submarine groundwater discharge), were consistent with independent measurements made with seepage meters. Eddy fluxes of heat were consistent with the balance of incoming solar radiation and thermal conduction at the sediment surface. Benthic eddy fluxes of fluorescent dissolved organic material (FDOM) revealed a substantial net downward flux in the humic-rich Concord River, suggesting that microbial consumption of dissolved organic carbon in the sediment was significant. Simultaneous measurement of several fluxes expands the utility of AEC as a biogeochemical tool while enabling checks for mutual consistency among data channels.

Authors: I. H. Hu, H. F. Hemond

Date Published: 20th Nov 2022

Publication Type: Journal Article

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