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New technologies in cancer mechanobiology

Scientific meeting

Starts:

June
202018

09:00

Ends:

June
212018

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Satellite meeting organised by Dr Chris Bakal and Dr Julia Sero

Melanoma cell spreading on collagen matrix. Credit: Chris Bakal and Oliver Inge

The development of new technologies has long been a driving force in the study of mechanobiology. This workshop will bring together an interdisciplinary group of early to senior level researchers to discuss cutting-edge in vivo, in vitro, and in silico techniques and how these methods can be applied to cancer research, diagnostics, and therapeutics.

Recorded audio of the presentations will be available on this page after the meeting has taken place. The speaker biographies and abstracts are available below. 

Enquires: Contact the Scientific Programmes team.

Event organisers

Select an organiser for more information

Schedule of talks

20 June

09:00-10:30

Session 1: Materials

6 talks Show detail Hide detail

09:05-09:15 Mechanobiology-based technology for rapid cancer diagnosis and prognosis

Professor Daphne Weihs, Technion-Israel Institute of Technology, Israel

Abstract

Metastasis requires cells to dynamically adapt to changing microenvironments and apply forces. Daphne Weihs shows that subpopulations of metastatic cells rapidly (<2 hours) and forcefully indent elastic, physiological stiffness, synthetic, impenetrable gels to depths of 1–20 µm, whereas benign/normal cells do not indent. The indenting subpopulation is highly migratory and invasive (Boyden chamber) and includes chemotherapy-resistant and cancer stem cells. Indentation capacity is governed by mechanobiology and is applicable to various solid cancers. Daphne will demonstrate with breast, pancreas, and skin cancers, rapid, same-day diagnosis and prognosis that matches the metastatic risk and clinical outcome in patients.

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09:15-09:30 Using mesoscopic models to understand the physical behaviours of cells and tissues

Dr Mike Murrell, Yale University, USA

Abstract

Living cells generate and transmit mechanical forces over diverse time-scales and length-scales to determine the dynamics of cell and tissue shape during both homeostatic and pathological processes. On the molecular scale, Mike Murrell’s group uses active gels as a framework to understand how mechanical stresses are transmitted within the cell cytoskeleton. On the scale of cells and tissues, they abstract these stresses to surface tensions in a liquid film and draw analogies between the dynamics of wetting to the shape dynamics of simple tissues. Together, they develop comprehensive descriptions for how cytoskeletal stresses translate to the physical behaviours of cells and tissues.

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09:30-09:45 Development of biomimetic stroma for 3D tumouroids

Dr Umber Cheema, University College London, UK

Abstract

There has been a drive to develop 3D models to test mechanisms of cancer progression. Such models aim to recapitulate specific aspects of the native microenvironment of cancer tissue. Umber Cheema’s group has developed 3D models of solid cancers, termed tumouroids. Using tissue engineering techniques, they control the spatial positioning of a cancer mass and its surrounding stroma. The group are able to engineer specific components into each component. They have engineered hypoxic gradients within the 3D model as well as engineering an intact primitive vascular network in the stromal component. They have observed interaction of cancer cells with engineered vascular networks- and measured angiogenic remodelling of the networks. By incorporating cancer associated fibroblasts from patient samples Umber is further investigating how these cells enhance cancer invasion and the mechanisms by which this is done.

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09:45-10:00 Mechanobiology in a microplate – opportunities for high throughput screening

Dr Chris Toseland, University of Kent, UK

Abstract

Mechanobiology focuses on understanding how physical forces correlate with protein, cell and tissue dynamics and organization through mechano-transduction. Single molecule force measurements have revealed how force is used in biological systems, from individual proteins to complexes. These changes occur through alteration of biochemical properties, yet such properties cannot be readily measured alongside force manipulation experiments. To this end Chris Toseland has developed a novel mechanobiology assay format to encompass mechanical measurements with biochemical and cellular assays using a modified microplate system. He demonstrates his group’s approach using force-induced in vitro enzymatic activity and conformation changes, along with receptor activation of signalling pathways in live cells.

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10:00-10:30 Discussion

Professor Daphne Weihs, Technion-Israel Institute of Technology, Israel
Dr Mike Murrell, Yale University, USA
Dr Umber Cheema, University College London, UK
Dr Chris Toseland, University of Kent, UK

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10:30-11:00 Coffee break

11:00-12:15

Session 2: Imaging

4 talks Show detail Hide detail

Sparks, waves, well-plates and 3D tissue culture: high speed light sheet fluorescence microscopy in space and time

Dr Chris Dunsby, Imperial College London, UK

Abstract

Light sheet fluorescence microscopy (LSFM) provides high speed low out-of-plane photobleaching and phototoxicity, but standard LSFM requires two microscope objective lenses orientated at 90° to one another to image the sample and this prevents imaging of conventional microscope slides and 96-well plates. Oblique plane microscopy (OPM) is an alternative approach that uses a single high numerical aperture microscope objective to provide both fluorescence excitation and detection, whilst maintaining the advantages of LSFM. Results of video-rate 3D imaging of calcium dynamics in cardiac myocytes and of cell migration in a 3D 96-well plate assay will be presented.

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11:00-11:15 Toward systems biophotonics: imaging biology across high spatio-temporal dimensions and scales

Dr Shu Jia, Stony Brook University, the State University of New York (SUNY), USA

Abstract

The distribution and interactions of single molecules in three-dimensionally organised cellular networks are fundamental to the function of living systems. Today, we still lack a complete understanding of how local molecular mechanisms are integrated and dynamically mapped over larger scales on to functional activities. The challenges pose high demands for imaging technologies to provide molecular specificity, nanometre-scale resolution, ultrafast speed, and accessibility across larger volumes of tissues. In this presentation, Shu Jia will talk about his laboratory’s recently developed super-resolution and light-field microscopy, and functional imaging tools for high-throughput extraction of molecular information in cells and tissues with ultrahigh-spatiotemporal resolution and accessibility.

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11:30-11:45 Multiparametric in vivo microscopy of tumour-microenvironment interactions

Dr Gert-Jan Bakker, Radboud Institute for Molecular Life Sciences, The Netherlands

Abstract

Third harmonic generation microscopy (THGM) is a versatile label free imaging modality for intravital microscopy, revealing discontinuities of the refractive index in the specimen and suited to visualise microvesicles, nerves, basement membranes, collagen structures and muscle fibres. Here, it is shown how optimised TGHM can be combined with second harmonics generation and multiphoton fluorescence microscopy. It is demonstrated that tissue structures of the tumour microenvironment assist guided migration, but also limit tumour cell migration by induction of nuclear damage. Finally, THGM imaging depth is extended into previously hidden areas of the tumour, by application of high pulse energy excitation sources.

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11:45-12:15 Discussion

Dr Shu Jia, Stony Brook University, the State University of New York (SUNY), USA
Dr Chris Dunsby, Imperial College London, UK
Dr Gert-Jan Bakker, Radboud Institute for Molecular Life Sciences, The Netherlands

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12:15-13:15

Lunch

13:15-14:30

Session 3: Cell mechanics

5 talks Show detail Hide detail

13:15-13:30 Mass spectrometry proteomics for mechanobiology

Dr Joe Swift, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK

Abstract

Proteins are the molecular machines that perform fundamental functional, structural and signalling roles in our cells and extracellular matrix. Protein regulation is therefore essential to the maintenance of tissue homeostasis, and the ability to measure the proteome can aid our understanding of ageing and disease processes. This presentation will examine how advances in label-free mass spectrometry proteomics can be applied to identify and quantify proteins in complex cell or tissue samples, and explore the relationship between proteins, mechano-signalling and mechanical properties.

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13:30-13:45 Motility, mechanics and microscopes: local activation of TRPV4 channel at focal adhesions mediates cell mechanosensing and migration

Dr Sergey Plotnikov, University of Toronto, Canada

Abstract

The ability of cells to migrate toward areas of higher extracellular matrix (ECM) rigidity, durotaxis, plays a key role in various physiological processes ranging from immune responses to embryo development. This ability is also central to pathological conditions such as inflammatory diseases and cancer. To understand how cells sample ECM rigidity to migrate along ECM stiffness gradients, Sergey Plotnikov characterised calcium signalling at integrin-based focal adhesions. Sergey shows that focal adhesions are centres of transient calcium sparks via mechano-gated ion channel TRPV4. He demonstrates that these sparks are driven by cellular actomyosin contractility and dynamic traction forces exerted by focal adhesions on the ECM. Sergey found that calcium sparks are increased in cells plated on soft ECM allowing local ECM stiffness probing. He also shows that calcium sparks regulate focal adhesion turnover as well as directed migration towards stiffer ECM. He concludes that local activation of TRPV4 channels regulated by ECM stiffness promotes selective disassembly of the focal adhesions attached to softer ECM and thus provides a gradient of focal adhesion turnover across a migrating cell, which mediates durotaxis.

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13:45-14:00 Probing epithelial mechanics in 3D

Professor Xavier Trepat, Institute for Bioengineering of Catalonia, Spain

Abstract

Biological processes such as morphogenesis, tissue regeneration, and cancer invasion are driven by collective migration, division, and folding of epithelial tissues. Each of these functions is tightly regulated by mechanochemical networks and ultimately driven by physical forces. Technologies to map of cell-cell and cell-extracellular matrix (ECM) forces during cell migration and division in a variety of epithelial models, from the expanding MDCK cluster to the regenerating zebrafish epicardium, will be presented. Direct measurements of epithelial traction, tension, and luminal pressure in three-dimensional epithelia of controlled size and shape will also be presented.

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14:00-14:30 Discussion

Dr Joe Swift, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK
Dr Sergey Plotnikov, University of Toronto, Canada
Professor Xavier Trepat, Institute for Bioengineering of Catalonia, Spain

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14:30-15:00 Tea

15:00-18:00

Session 4: Modelling

5 talks Show detail Hide detail

15:00-15:15 Tracing actin polarity in cellular networks

Dr Matthias Eibauer, University of Zurich, Switzerland

Abstract

The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. In order to understand these processes, the directionality of actin filaments and their interactions with binding partners are of major importance. In this talk, Matthias Eibauer discusses how his team developed the means to detect actin directionality within unlabelled filamentous networks. This approach is based on cryo-electron tomography in conjunction with image processing. This method can be adopted to reveal the polarity and binders of actin filaments in cells and at physiological cellular processes.

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15:15-15:30 Multiscale models to uncover the systems-mechanobiology of cancer

Dr Fabian Spill, University of Birmingham, UK

Abstract

The field of mechanobiology uncovered a large number of ways how mechanical properties or forces may affect intracellular signalling pathways, eg through conformal deformations of proteins or the opening of ion gates. Such pathways, in turn, may also regulate the cytoskeleton or other mechanically active components of cells, leading to mechanochemical feedbacks. In this talk, mathematical modelling approaches are discussed that describe different aspects of mechanobiology. For instance, ODE models are employed to understand the pathway dynamics, PDE models are used to understand the effect of spatial localisation of signalling molecules, and stochastic models are used to describe the force-dependent dynamics of adhesion binding. Fabian Spill finally outlines approaches to combine different models, eg adhesion dynamics with cell and tissue forces, to gain a systems-level understanding of the mechanobiology of cancer.

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15:30-15:45 Reverse engineering cell competition

Professor Guillaume Charras, University College London, UK

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15:45-16:00 Discussion

Dr Matthias Eibauer, University of Zurich, Switzerland
Professor Guillaume Charras, University College London, UK

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16:00-18:00 Breakout sessions I

21 June

09:30-10:30

Session 5: Cell-cell interactions I

5 talks Show detail Hide detail

09:30-09:45 Cell motility and extracellular basement membrane development in a model of breast development and breast cancer

Dr Claire Robertson, Lawrence Berkeley National Lab, USA

Abstract

Loss of the basement membrane is a hallmark of invasive cancer. Claire Robertson’s group studies how basement membrane develops by culturing nonmalignant breast epithelial cells (BEC), which develop into polarized, growth arrested structures to malignant breast cancer cells (BCC), which form disorganised masses under the same conditions. These two cell types show different movement patterns in the ECM gels: BEC rotate around their centre of mass in a process termed coherent angular motion, whereas BCC migrate randomly. Coherent angular motion appears to affect concentration of exogenous ECM by physically pulling ECM proteins into an organised shell at the cell surface as an early aspect of formation of a basement membrane-like ECM structure in mammary epithelial cells in culture, whereas this process is defective in malignant cells undergoing random motility.

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09:45-10:00 CAFs: useful cellular models to investigate cancer mechanobiology

Dr Fernando Calvo, Institute of Biomedicine & Biotechnology of Cantabria, Spain

Abstract

Cancer-associated fibroblasts (CAFs) are predominant non-malignant cells in tumours that actively remodel the extracellular matrix thereby affecting the physical properties of solid tumours. Fernando Calvo will show technologies to assess CAF function in cancer and how he has used them to unveil important aspects of cancer mechanobiology. In addition, he will discuss how he has used CAFs to decipher the molecular mechanisms governing mechanotransduction, and their impact in CAF behaviour and cancer progression.

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10:00-10:15 YAP/TAZ in development, regeneration, and cancer

Dr Barry Thompson, Francis Crick Institute, UK

Abstract

The YAP and TAZ transcriptional co-activators drive TEAD-dependent transcription to promote cell proliferation during normal development, tissue regeneration, and cancer. Barry Thompson will describe how YAP/TAZ are regulated by growth factor signalling, the Hippo pathway, mechanical forces and tissue damage in epithelia. He will further describe genetic loss-of-function and gain-of-function analysis of YAP/TAZ in both Drosophila and mice, and the implications of these findings for various types of human cancer.

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10:15-10:30 Discussion

Dr Claire Robertson, Lawrence Berkeley National Lab, USA
Dr Fernando Calvo, Institute of Biomedicine & Biotechnology of Cantabria, Spain

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10:30-11:00 Coffee

11:00-12:00

Session 6: Cell-cell interactions II

3 talks Show detail Hide detail

11:00-11:15 Fast super-resolution imaging without artefacts

Dr Susan Cox, King's College London, UK

Abstract

Conventional localisation microscopy relies on sparse activation of flurophores to allow accurate data fitting, meaning acquisition is slow and live cell experiments difficult or impossible. Several algorithms have been developed to cope with high emitter density. However, these produce significant image artefacts as the density is increased, which are easily mistaken for high resolution. By examining known biological structures it is shown that artefacts can be largely eliminated by pre-processing the image sequence with a succession of Haar wavelet kernels (HAWK), improving the resolving power and ensuring that the image reflects the structure of the sample.

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11:15-11:30 Next-generation spatial RNA sequencing technologies

Dr Je H Lee, Cold Spring Harbor Laboratory, USA

Abstract

Tumour growth is regulated by cell autonomous as well as short- and long-range cell-cell interactions. The Lee group has been developing methods to label, track, and isolate single cells and their gene expression products in tumour tissues, including sequencing of somatic mutations, lineage reporters, and transcriptional markers. First, the talk will focus on a high-sensitivity in situ sequencing method for fluorescently labelling single cells and their applications in cancer medicine. Second, the talk will present paired-end DNA sequencing chemistry for 3D transcriptome reconstruction of developing tissues, concluding with discussing ways to study genotype-phenotype correlations in vivo.

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11:30-12:00 Discussion

Dr Susan Cox, King's College London, UK
Dr Je H Lee, Cold Spring Harbor Laboratory, USA

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12:00-14:00

Lunch with Breakout sessions II

Related events

New technologies in cancer mechanobiology

Satellite meeting organised by Dr Chris Bakal and Dr Julia Sero

Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ