ERC Advanced Grant 741350
What Holds Cancer Cells Back?
in context of H2020
Since decades the bulk of cancer research focusses on the genetic and molecular level. To
complement this knowledge, I will focus on the collective behaviour of cancer cells in cell clusters and
in the extracellular matrix (ECM).
Conventional cancer research tackles issues like genetic changes, signalling pathways or intracellular
mechanisms. In contrast, I want to answer the fundamental, mechanistic question: When is a cancer
cell jammed or when can it overcome the yield stress to actively „flow“ in a dense
microenvironment (ME)? Within the concept of Physics of Cancer, I have brought forward the idea
that changes in a cancer cell’s material properties determine its metastatic potential. To build upon this
I propose the next breakthrough by determining a predictive phase diagram for unjamming transitions
of cancer cells.
Cancer cell jamming is quantified by cell speed as a measure of the motile forces and by cellular shape
to account for the interplay between cell contractility and adhesion. Our self-propelled Voronoi model
(SPV) will conclusively explain whether a cell is jammed by its neighbours or the ECM, thereby
overcoming the limitations of existing theories which only apply to specific environments.
Building on my leadership in cell biomechanics and the exclusive clinical access to two types of
carcinomas (mamma, cervix), I will introduce highly innovative bionic modulators of intracellular
mechanics and develop live cancer cell tracking in biopsies as a ground-breaking alternative to vital
imaging. While these approaches are perfect to prove that unjamming transitions are key to tumour
progression, I will investigate to what extent fluid, i.e. unjammed, tissue behaviour can be detected by
magnetic resonance imaging elastography (MRE) as an individual predictive marker for metastasis.
Moreover, the results may guide surgeons when considering the local spreading of cancer and thus
greatly empower surgery in tumour therapies.
Physics of Cancer
The aim of this symposium is by bringing together exceptional researchers in the
areas of quantitative cell biology, physical mechanisms of pathology, cancer biology,
molecular design, diagnostic systems and beyond to create a forum for the exchange of
new ideas and formulation of new solutions.
F Sauer, L Oswald, A Ariza de Schellenberger, H Tzschätzsch, F Schrank, T Fischer,
J Braun, CT Mierke, R Valiullin, I Sack, JA Käs:
Collagen networks determine viscoelastic properties of connective
tissues yet do not hinder diffusion of the aqueous solvent
Abstract:>Collagen accounts for the major
extracellular matrix (ECM) component in many tissues and provides mechanical support for cells.
Magnetic Resonance (MR) Imaging, MR based diffusion measurements and MR Elastography (MRE) are
considered sensitive to the microstructure of tissues including collagen networks of the ECM.
However, little is known whether water diffusion interacts with viscoelastic properties of tissues.
This study combines highfield MR based diffusion measurements, novel compact tabletop MRE and
confocal microscopy in collagen networks of different cross-linking states (untreated collagen
gels versus additional treatment with glutaraldehyde). The consistency of bulk rheology and MRE
within a wide dynamic range is demonstrated in heparin gels, a viscoelastic standard for MRE.
Additional crosslinking of collagen led to an 8-fold increased storage modulus, a 4-fold increased
loss modulus and a significantly decreased power law exponent, describing multi-relaxational behavior,
corresponding to a pronounced transition from viscous-soft to elastic-rigid properties. Collagen network
changes were not detectable by MR based diffusion measurements and microscopy which are sensitive to the
micrometer scale. The MRE-measured shear modulus is sensitive to collagen fiber interactions which take
place on the intrafiber level such as fiber stiffness. The insensitivity of MR based diffusion measurements
to collagen hydrogels of different cross-linking states alludes that congeneric collagen structures in
connective tissues do not hinder extracellular diffusive water transport. Furthermore, the glutaraldehyde
induced rigorous changes in viscoelastic properties indicate that intrafibrillar dissipation is the dominant
mode of viscous dissipation in collagen-dominated connective tissue.
Soft Matter, 15, 3055-3064 (2019), DOI: 10.1039/C8SM02264J
CT Mierke, F Sauer, S Grosser, S Puder, T Fischer, JA Käs:
The two faces of enhanced stroma: Stroma acts as a tumor promoter
and a steric obstacle
Abstract: In addition to genetic,
morphological and biochemical alterations in cells, a key feature of the malignant
progression of cancer is the stroma, including cancer cell motility as well as the
emergence of metastases. Our current knowledge with regard to the biophysically driven
experimental approaches of cancer progression indicates that mechanical aberrations
are major contributors to the malignant progression of cancer. In particular, the
mechanical probing of the stroma is of great interest. However, the impact of the
tumor stroma on cellular motility, and hence the metastatic cascade leading to the
malignant progression of cancer, is controversial as there are two different and
opposing effects within the stroma. On the one hand, the stroma can promote and
enhance the proliferation, survival and migration of cancer cells through
mechanotransduction processes evoked by fiber alignment as a result of increased
stroma rigidity. This enables all types of cancer to overcome restrictive biological
capabilities. On the other hand, as a result of its structural constraints, the stroma
acts as a steric obstacle for cancer cell motility in dense three-dimensional extracellular
matrices, when the pore size is smaller than the cell´s nucleus. The mechanical properties
of the stroma, such as the tissue matrix stiffness and the entire architectural network of
the stroma, are the major players in providing the optimal environment for cancer cell migration.
Thus, biophysical methods determining the mechanical properties of the stroma, such as magnetic
resonance elastography, are critical for the diagnosis and prediction of early cancer stages.
Fibrogenesis and cancer are tightly connected, as there is an elevated risk of cancer on cystic
fibrosis or, subsequently, cirrhosis. This also applies to the subsequent metastatic process.
NMR Biomed., vol. 10, e3831 (2018), DOI: 10.1002/nbm.3831
T Golde, C Huster, M Glaser, T Händler, H Herrmann, JA Käs, J Schnauß:
Glassy dynamics in composite biopolymer networks
Abstract: The cytoskeleton is a highly interconnected meshwork of strongly coupled
subsystems providing mechanical stability as well as dynamic functions to cells.
To elucidate the underlying biophysical principles, it is central to investigate not only
one distinct functional subsystem but rather their interplay as composite biopolymeric structures.
Two of the key cytoskeletal elements are actin and vimentin filaments. Here, we show that composite
networks reconstituted from actin and vimentin can be described by a superposition of two
non-interacting scaffolds. Arising effects are demonstrated in a scale-spanning
frame connecting single filament dynamics to macro-rheological network properties.
The acquired results of the linear and non-linear bulk mechanics can be captured
within an inelastic glassy wormlike chain model. In contrast to previous studies,
we find no emergent effects in these composite networks. Thus, our study paves the
way to predict the mechanics of the cytoskeleton based on the properties of its single
Soft Matter vol. 14, 7970-7978 (2018),
F Meinhövel, R Stange, J Schnauß, M Sauer, JA Käs, TW Remmerbach:
mechanics - a precondition for malignant transformation of oral squamous
Abstract: Oral squamous cell
carcinomas (OSCC) are the sixth most common cancer and the diagnosis is often
belated for a curative treatment. The reliable and early differentiation between
healthy and diseased cells is the main aim of this study in order to improve
the quality of the treatment and to understand tumour pathogenesis. Here, the
optical stretcher is used to analyse mechanical properties of cells and their
potential to serve as a marker for malignancy. Stretching experiments revealed
for the first time that cells of primary OSCCs were deformed by 2.9% rendering
them softer than cells of healthy mucosa which were deformed only by 1.9%.
Furthermore, the relaxation behaviour of the cells revealed that these malignant
cells exhibit a faster contraction than their benign counterparts. This suggests
that deformability as well as relaxation behaviour can be used as distinct
parameters to evaluate emerging differences between these benign and malignant
cells. Since many studies in cancer research are performed with cancer cell
lines rather than primary cells, we have compared the deformability and
relaxation of both types, showing that long time culturing leads to softening
of cells. The higher degree of deformability and relaxation behaviour can
enable cancer cells to traverse tissue emphasizing that changes in cell
architecture may be a potential precondition for malignant transformation.
Respecting the fact that even short culture times have an essential effect
on the significance of the results, the use of primary cells for further
research is recommended. The distinction between malignant and benign cells
would enable an early confirmation of cancer diagnoses by testing cell samples
of suspect oral lesions.
Convergent Science Physical Oncology, vol. 4, 034001(2018),
J Lorenz, J Schnauß, M Glaser, M Sajfutdinow, C Schuldt, JA Käs, DM Smith:
Synthetic Transient Crosslinks Program the Mechanics of Soft, Biopolymer-Based
Abstract: Actin networks are
adaptive materials enabling dynamic and static functions of living cells.
A central element for tuning their underlying structural and mechanical properties
is the ability to reversibly connect, i.e., transiently crosslink, filaments within
the networks. Natural crosslinkers, however, vary across many parameters. Therefore,
systematically studying the impact of their fundamental properties like size and
binding strength is unfeasible since their structural parameters cannot be independently
tuned. Herein, this problem is circumvented by employing a modular strategy to construct
purely synthetic actin crosslinkers from DNA and peptides. These crosslinkers mimic both
intuitive and noncanonical mechanical properties of their natural counterparts. By
isolating binding affinity as the primary control parameter, effects on structural and
dynamic behaviors of actin networks are characterized. A concentration-dependent
triphasic behavior arises from both strong and weak crosslinkers due to emergent
structural polymorphism. Beyond a certain threshold, strong binding leads to a nonmonotonic
elastic pulse, which is a consequence of self-destruction of the mechanical structure of
the underlying network. The modular design also facilitates an orthogonal regulatory
mechanism based on enzymatic cleaving. This approach can be used to guide the rational
design of further biomimetic components for programmable modulation of the properties
of biomaterials and cells.
Advanced Materials 1706092 (2018), DOI: 10.1002/adma.201706092
L Oswald, S Grosser, DM Smith, JA Käs:
Jamming transitions in cancer
Abstract: The traditional
picture of tissues, where they are treated as liquids defined by properties
such as surface tension or viscosity has been redefined during the last
few decades by the more fundamental question: Under which conditions do
tissues display liquid-like or solid-like behaviour? As a result, basic
concepts arising from the treatment of tissues as solid matter, such as
cellular jamming and glassy tissues, have shifted into the current focus
of biophysical research. Here, we review recent works examining the phase
states of tissue with an emphasis on jamming transitions in cancer. When
metastasis occurs, cells gain the ability to leave the primary tumour and
infiltrate other parts of the body. Recent studies have shown that a linkage
between an unjamming transition and tumour progression indeed exists, which
could be of importance when designing surgery and treatment approaches
for cancer patients.
Journal of Physics D: Applied Physics, Volume 50, 483001 (2017),
D Strehle, P Mollenkopf, M Glaser, T Golde, C Schuldt, JA Käs, J Schnauß:
Single Actin Bundle Rheology
structures play an essential role in the mechanical response of the actin
cytoskeleton in eukaryotic cells. Although responsible for crucial cellular
processes, they are rarely investigated in comparison to single filaments
and isotropic networks. Presenting a highly anisotropic structure, the
determination of the mechanical properties of individual bundles was previously
achieved through passive approaches observing bending deformations induced
by thermal fluctuations. We present a new method to determine the bending
stiffness of individual bundles, by measuring the decay of an actively
induced oscillation. This approach allows us to systematically test anisotropic,
bundled structures. Our experiments revealed that thin, depletion force-induced
bundles behave as semiflexible polymers and obey the theoretical predictions
determined by the wormlike chain model. Thickening an individual bundle
by merging it with other bundles enabled us to study effects that are solely
based on the number of involved filaments. These thicker bundles showed
a frequency-dependent bending stiffness, a behavior that is inconsistent
with the predictions of the wormlike chain model. We attribute this effect
to internal processes and give a possible explanation with regard to the
wormlike bundle theory.
Molecules 22(10) 1804 (2017),