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Project Stories: Guillermo Vilanova

When mathematical and computational models join forces with mechanobiology. This is a great statement to start this interview. Guillermo Vilanova is a PostDoc working together with Marino Arroyo at UPC. His aim within the Mechano·Control project is to develop a mathematical and computational framework to study the tightly coupled evolution of cancerous organoids and collagen matrix from a mechanical perspective. Let’s dive into the mathematical world and how it is connected with mechanobiology.

One of the aims of the Mechano·Control project is to achieve the mechanical control of the biological function with the aim to abrogate breast tumour progression. To meet this end, it is important to unravel the role of mechanical forces and cell mechanosensation in breast cancer invasion. To do that, Guillermo and the team at UPC are developing a mathematical and computational framework towards the understanding of the physical principles that drive this invasion.

In ductal carcinoma, cancerous cells aggregate to form three-dimensional tumors in the ducts of the breast and may show a highly invasive behavior under certain conditions. Until now, the specific conditions under which ductal carcinoma becomes invasive has been elusive. The role of the extracellular matrix is being broadly studied and it has been demonstrated that it plays a crucial role in enhancing cell invasion towards other parts of the body.

Thanks to their collaborators’ latest experiments, they have proposed a mechanism for cancer invasion that views this phenomenon as a spontaneous pattern formation, and hence does not require that, by an unknown process, some specific cells change their nature and become leaders of invasion. Instead, the invading tumor self-organizes through a feedback between cellular mechanosensing and matrix mechanics. For this reason, Guillermo is currently working in developing more accurate models and simulations of this process to understand the mechanical basis of cancer invasion.

Left panel: The mathematical model is based on the phase-field theory, that allows us to model cancer cells as an active, mechanosensitive fluid and the extracellular matrix as a non-linear solid. Center panel: The coupling between the solid and the fluid is straightforward using a total Lagrangian description. Right panel: With these modelling strategies we can recapitulate cancer invasion through symmetry breaking (left) and long-range communication between organoids (right).

To this end, he is developing a mathematical model very similar to those used in the computation of forces in inert systems, like the models used to compute the forces that a pillar of a bridge needs to support. In biology, however, the challenge is that we deal with live and active systems, rather than inert. For instance, breast cancer cells can “sense” mechanical forces that are transmitted through the extracellular matrix and actively respond to them by changing their migration direction.

“Our mathematical model extends the classical equations for inert materials to incorporate these active mechanosensitive responses, the nonlinear behavior of the collagen-rich extracellular matrices and their complex coupling.”

Explains Guillermo Vilanova.

This mathematical model has two purposes: rationalize the observations made by their collaborators in their experiments and use this model as a predictive tool.

And how do they do that? On the one hand, by solving the equations of the mathematical theory in supercomputers to create simplified virtual replicas of the experimental setups. Then, by altering the conditions of these in silico experiments, they can understand what the key ingredients of the mathematical model are and thus, the driving forces of breast cancer invasion.

On the other hand, to use this mathematical framework as a predictive tool, thanks to the supercomputers, the researchers can create virtual playgrounds to test hypothesis and to unravel new mechanisms that can then be tested experimentally.

Two-dimensional study of the relative positioning of two populations of breast cancer cells (read and green) within the extracellular matrix (grey).
An organoid composed by two populations of cancer cells (red and green) moves driven by gradients of stiffness in the extracellular matrix (grey).

And which will be the expected results of these objectives? Again, we have two ambitious goals: address the importance of the relative positioning of cells within the tumor and unravel how cell mechanosensitivity and extracellular matrix mechanics interact to determine whether a tumor becomes invasive or not.

“The answer to these questions may deepen the knowledge we have on the role of mechanics in cancer invasion and may serve as a tool to ultimately prevent the invasion of breast cancer by altering the mechanical pathways.”

Adds Guillermo Vilanova

In order to understand and control how cells transmit and detect mechanical forces, it is important to take a look at every scale and use all the tools available. According to Guillermo, it is very exciting to be a part of this multidisciplinary and ambitious project that tries to answer such interesting and challenging questions. Although each member has specific expertise in different scientific fields and scales, we are working hand by hand in the same direction, so that by joining all the pieces we may finally solve the full puzzle. “It is extremely motivating to collaborate with people with different backgrounds that complement each other,” adds Guillermo.

Predicting whether chemo will be effective for breast cancer

Breast cancer researchers at UMC Utrecht have discovered that a certain protein can predict whether a course of chemo will be effective for aggressive breast cancer. Women with breast cancer and a high level of FER protein have a greater chance of successful treatment with taxane chemotherapy. The results of this study were published in the renowned scientific journal Cell Reports.

Triple-negative breast cancer is an aggressive type of breast cancer. Women with triple-negative breast cancer often receive treatment with chemotherapy. The goal of the chemotherapy is to reduce the risk of metastasis (spread of the cancer) as far as possible, which increases the chances of survival.

The treatment with chemotherapy is not equally effective for all women. Many women also often suffer unpleasant side effects, such as fatigue, anemia, nausea, and hair loss. “It would be really helpful if we could predict whether a treatment with chemotherapy will be effective,” explains Patrick Derksen, professor of pre-clinical oncology at UMC Utrecht.

High FER protein, greater benefit of chemotherapy

His research group discovered that a certain protein could predict whether a course of chemo will be effective for triple-negative tumors. Women with breast cancer and high levels of the so-called “FER protein” will benefit more from treatment with chemotherapy.

Specifically, they will benefit from chemotherapy with taxanes, a type of medication that slows down cell division. “The FER protein basically recycles other proteins that the cancer cells need to be able to spread,” Derksen explains. “The taxanes slow down this process.”

Test that indicates whether chemotherapy will be beneficial

The researchers are now working on developing a test that demonstrates whether a triple-negative breast tumor has high or low levels of FER protein. High levels of FER equate to a greater probability of the taxane chemotherapy being effective.

Derksen: “We want to start using the test right from the moment of diagnosis, so that we can offer a more tailored treatment. The test is performed in the lab on collected tumor material. We do not need to ask the patients to do anything extra. We will conduct clinical trials on this test, to confirm our prediction and so be able to offer a more personalized and effective treatment.”

Further information

Source: UMCUtrecht

Mechanobiology of Cancer Summer School 2022

Mechanobiology of Cancer Summer School 2022

The MECHANO·CONTROL consortium, led by several research institutions across Europe, is launching the second edition of the “Mechanobiology of Cancer Summer School” which will take place between September 27th – October 1st 2022 at the Eco Resort in La Cerdanya. The aim of the summer school is to provide training on mechanobiology, and specifically its application to cancer. This school will include lectures as well as practical workshops in different techniques and disciplines, ranging from modelling to biomechanics to cancer biology.

The first edition was a great success, both in participation and scientific level, with more than 60 people from 13 different countries.

Mechanobiology of Cancer Summer School 2019

During this second edition, there will be scientific sessions in the morning, mixing 6 keynote speakers with 18 short talks selected from abstract submissions by junior scientists attending the school. In the afternoon, there will be 2-3-hour practical workshops, given by scientists from the MECHANO·CONTROL consortium. The course will also include leisure activities.

Attendance to the Summer School is open to all students, post-docs, and professionals interested, although priority will be given to junior scientists (up to post-doctoral stage).

You can visit the Mechanobiology of Cancer Summer School 2022 website, where you will find more information about the activities that will be held during the summer school, information on how to register, and the deadlines both for the registration and abstract submission.

The 6 confirmed speakers who will attend the summer school are:

  • Dagmar Iber (ETH Zurich)
  • Hans Van Oosterwyck (KU Leuven)
  • Claudia Fischbach (Director of Cornell’s Physical Sciences Oncology)
  • Giorgio Scita (IFOM – The Firc Institute Of Molecular Oncology)
  • Madeleine J. Oudin (Tufts University)
  • Maria Celeste Aragona (University of Copenhagen)

Also, all MECHANO·CONTROL consortium members will be attending the summer school and will be giving some of the whorkshops: Aránzazu del Campo (Leibniz-Institut für Neue Materialien, INM), Sergi Garcia-Manyes (King’s College London, KCL), Pere Roca-Cusachs and Xavier Trepat (Institute for Bioengineering of Catalonia, IBEC), Patrick Derksen, Antoine Khalil and Johan de Rooij (University Medical Center Utrecht, UMCU) and Marino Arroyo (Universitat Politècnica de Catalunya, UPC).

Preliminary list of workshop topics:

  • Vertex modelling mechanics
  • Single molecule mechanics
  • Fundamentals of breast cancer biology
  • Chemistry of tuneable gels

Don’t miss this great networking opportunity, where you will meet and interact with experts in the mechanobiology field and meet new people to collaborate with in the future!

About MECHANO·CONTROL

TheMECHANO·CONTROL project is focused on the mechanical control of biological function.Mechanical forces transmitted through specific molecular bonds drive biological function, and their understanding and control hold an uncharted potential in oncology, regenerative medicine and biomaterial design.

MECHANO·CONTROL proposes to address this challenge by building an interdisciplinary research community with the aim of understanding and controlling cellular mechanics from the molecular to the organism scale. At all stages and scales of the project, it will integrate experimental data with multi-scale computational modelling to establish the rules driving biological response to mechanics and adhesion. With this approach, it aims to explore novel therapeutic approaches beyond the current paradigm in breast cancer treatment. If the partners can understand cancer biomechanics from the single molecule to the whole organ scale, they’ll be able to control mechanical forces to restore healthy cell behaviour and inhibit tumour progression.

Beyond breast cancer, the general principles targeted by this technology will have high applicability in oncology, regenerative medicine, biomaterials and many other biological processes and diseases.

MECHANO·CONTROL is a project funded by the European Commission, within the Future and Emerging Technologies (FET) proactive program.

Researcher Xavier Trepat wins the “Constantes y Vitales” award for his pioneering contributions to the mechanobiology field

Researcher Xavier Trepat wins the “Constantes y Vitales” award for his pioneering contributions to the mechanobiology field

Xavier Trepat, ICREA research professor and group leader at the Institute for Bioengineering of Catalonia (IBEC), has been awarded the “Young Talent Award in Biomedical Research”. The ceremony took place at the Palacio de las Alhajas Mamen Mendizábal, Madrid, with the presence of the Minister of Science and Innovation, Diana Morant, and the Chief Executive Officer of Atresmedia, Silvio González. This is the 7th edition of the “Constantes y Vitales” Awards which is aimed at recognizing the 2021 projects in Biomedical Research and Health Prevention.
Xavier Trepat at the awarding ceremony

Xavier Trepat, leader of the research group Integrative cell and tissue dynamics at IBEC, and member of CIBER-BBN, is a recognized expert and pioneer, at an international level, in the field known as mechanobiology, which studies the role of physics in biological systems. Trepat and his team have developed several technologies over the past decade that have made it possible to observe, and measure at the nano-scale, the properties of cells. In doing so, Trepat and his team have contributed to a better understanding of the fundamental mechanisms underlying cell interaction and communication and have reported astonishing discoveries such as that of super elastic cells. 

But this researcher, an engineer by training, had also a close experience working at a hospital where research was carried out changed the way of understanding science, has also focused on the role of physics in disease. As he stated in a recent article in Nature, the mechanical properties of tissues also play a role in abnormal cell growth, such as in cancer. In Trepat’s own words, “Rigidity makes cancer cells more malignant.” 

And it is that mechanical forces determine biological entities such as cells and organs, both in health and disease and, therefore, as Trepat points out, “Understanding a cell without physics is like trying to write a book with only half the letters of the alphabet”. 

As an example, Trepat and his collaborators recently used mouse stem cells, together with bioengineering and mechanobiology techniques, to measure, for the first time, cellular forces in laboratory mini-intestines. Thanks to this, the team led by Trepat was able to decipher how the inner wall of the intestine folds and moves. The study, published in the journal Nature Cell Biology, opened the doors to understand the bases of diseases such as celiac disease or cancer, and to find solutions for intestinal pathologies through the development of new therapies. 

Awards for an exceptional international career

The European Research Council (ERC) – a European public organization that finances research projects – awarded Xavier Trepat, in 2020, the prestigious ERCAdvancedGrant, endowed with 2.5M euros. Before obtaining this scholarship, the researcher also obtained the “StartingGrant”, “ConsolidatorGrant” and “ProofofConcept” grants, all of them awarded by the ERC, completing the largest series of distinctions at the international level of this entity. 

Previously, in 2015, Trepat was awarded with the Banco Sabadell Award, one of the most important grants in Spain, in the field of health sciences. 

Xavier Trepat has also been one of the few researchers who have managed to publish his work, as first author, in five journals of the Nature family, specifically in Nature, Nature Physics, Nature Materials, Nature Methods, and Nature Cell Biology. 

Research uncovers how damaged nucleus re-seals and repairs itself

Research uncovers how damaged nucleus re-seals and repairs itself

The new study shows the molecular mechanisms which re-seal the nucleus’ protective envelope to shield its genetic material.

Within a cell, the nucleus is surrounded by the nuclear envelope – two layers of phospholipid membrane that prevents the nucleus mixing with other parts of the cell, thus protecting the cell’s DNA from outside damage.

However, the nuclear envelope is sometimes broken and ruptured when it undergoes strain. This can occur when the cytoskeleton (a network of fibres acting as a scaffold and give it a stable structure) exerts pressure on the nucleus.

A new study, led by Dr Monica Agromayor of the School of Immunology & Microbial Sciences, illuminates how pressure is relieved from the cytoskeleton.

Uncovering the mechanisms that underpin rupture repair is a fundamental question in cell biology, and a better understanding of this process has broad implications for human diseases such as cancer, cardiovascular disease, or autoimmunity

Dr Monica Agromayor, School of Immunology & Microbial Sciences

Research indicates that a group of proteins known as the ESCRT machinery is responsible for re-sealing the nuclear envelope.

The paper, published in Developmental Cell, focuses on a protein associated with ESCRT named BROX. It shows that BROX is the key protein in relieving pressure from the cytoskeleton, thereby allowing the nuclear envelope to re-seal.

The ESCRT machinery attaches BROX to the site of rupture on the envelope. This allows BROX to bind to the LINC complex – a group of proteins that connect the nuclear envelope to the cytoskeleton, allowing it to apply excessive pressure on the nuclear envelope.

BROX binding leads to LINC being removed from the rupture site. This reduces the stress enforced by the cytoskeleton, allowing the nuclear envelope to repair itself.

The results support growing evidence that the nucleus is an organelle that can interact with its cellular environment, as opposed to just being a protective case for DNA.

Significantly, these results could also have implications for cancer research as a damaged nuclear envelope is associated with cardiovascular diseases and cancer. For example, BROX gene mutations have been found in familial nonmedullary thyroid cancer. Future research can investigate whether BROX mutations contribute to tumours.

Speaking about the team that conducted the research Dr Monica Agromayor said: “This multidisciplinary work shows the importance of collaborative research. Besides the close collaboration with Juan Martin-Serrano, we were fortunate to join forces with the laboratory of Sergi Garcia Manyes from the Physics Department at King’s.”

Read the full paper ‘The ESCRT machinery counteracts Nesprin-2G-mediated mechanical forces during nuclear envelope repair’ in Developmental Cell.

Original source: KCL

Researchers discover how cellular membranes change curvature depending on BAR proteins

Researchers from both Pere Roca-Cusachs and Marino Arroyo labs, study how BAR proteins, a family of molecules that bind curved cellular membranes, reshape these membranes. Scientists report in the journal Nature Communications, through both experiments and modelling, the dynamics of these membrane reshaping processes that occur both in normal cells or disease scenarios.

Simulations of a membrane tube (600nm diameter) dynamically reshaped by a BAR protein.

The human body is a complex mosaic made up of a very large number of cells with different properties, but they all share a common feature: they possess an external envelope (also called membrane), which is curved at the micrometer and nanometer scales.

During essential cell functions like migration, endo/exocytosis, or when they are deformed by external forces, cell membranes constantly change shape. Here, BAR proteins play a fundamental role. However, the dynamics and mechanochemistry of the process was not well understood until now.

Now, a group of researchers at the Institute for Bioengineering of Catalonia (IBEC) and at the Polytechnical University of Catalonia (UPC) publish new results in the Journal Nature Communications, providing a foundation to understand several processes of membrane deformation, that occur both in normal cell physiology and in disease scenarios. Specifically, researchers describe novel reshaping events of low-curvature membrane structures by BAR proteins, which were previously not considered. Researchers also show how mechanically deforming the membrane triggers a biochemical response mediated by BAR proteins.

The key to understand cell membranes and their curvature 

Experimentally, researchers developed an in vitro system to mechanically deform artificial membranes, expose them to purified BAR proteins, and observed the resulting dynamics by confocal microscopy. In addition, researchers developed theoretical models to understand the process, capturing the dynamics and mechanochemistry of the process. Combining both, experimental and theoretical approaches, researchers also observed that cell membrane deformations depend on initial membrane shape.

Anabel-Lise le Roux (IBEC) and Caterina Tozzi (UPC), co-first authors of the study, explain the importance of having both experimental and theoretical approaches to understand such complex deformation processes.

“The really tight interaction between experiments and modelling was essential to deeply understand a very complex mechanochemical process”.

Anabel-Lise Le Roux and Caterina Tozzi.

The work published in Nature Communications was senior-authored by Marino Arroyo (UPC) and Pere Roca-Cusachs (IBEC/UB).

Reference article: Anabel-Lise Le Roux, Caterina Tozzi, Nikhil Walani , Xarxa Quiroga, Dobryna Zalvidea, Xavier Trepat, Margarita Staykova, Marino Arroyo, Pere Roca-Cusachs. Dynamic Mechanochemical feedback between curved membranes and BAR protein self-organization. Nat Commun 12, 6550 (2021).

Project stories: interview with Thijs Koorman

Project stories: interview with Thijs Koorman

The ultimate goal of the Mechano·Control project is to be able to abrogate breast tumour progression. To do that, it is very important to apply the Mechano·Control findings at different scales, from single molecules and all the way up to the organism and patient level. For that, Thijs Koorman, a senior postdoc at the DerksenLab at the UMC Utrecht, will perform fundamental  and preclinical research within in the Mechano Control project. His main goal is to translate basic findings with therapeutic potential to target invasive breast cancer. With this interview, we are going to take a step forward and get a closer look to the animal and human models, the largest scale of the Mechano·Control consortium.

Dr. Thijs Koorman runs a variety of different tasks. But first, let’s get to know a little bit more about their role in the Mechano·Control consortium. The main aim within the DerksenLab  is to translate the molecular findings within the Mechano·Control project to animal and human models of invasive breast cancer. This group has a fundamental to translational focus. They provide proof of concept in preclinical models of breast cancer and test novel candidate targeted therapeutic interventions identified within Mechano·Control.

With this in mind, Thijs together with Dr. Daan Visser (technician within the Mechano Control consortium) test the therapeutic potential of the identified molecules in the consortium with the hope to obtain pre-clinical data that can be used to ultimately better treat patients suffering from invasive breast cancer.

And how is this translated into the lab?

“We culture mouse and human organotypic cancer models in both 2D and 3D. The models used represent the two types of invasive breast cancer. As such, they harbour all aspects of human invasive breast cancer, which we study using molecular biochemistry and microscopy”, explains Thijs.       

In particular, Thijs studies the molecular and signalling composition of cell adhesion proteins and how disruption of this complex potentiates oncogenic signalling. For this he uses 2D and 3D organotypic tumor models and preclinical mouse models of invasive breast cancer. The group has a deep interest in how loss of mechano-transducing cell-cell and cell-matrix contacts drive to invasive breast cancers, focussing on lobular carcinoma. The groups has generated a breast cancer sample database of over 2000 patients and collected tumour material of over >1000 patients to test molecular markers.

LEFT PANEL: Multiple examples of breast cancer samples, punched from human invasive breast cancers as spotted as a micro-array cores. Top two cores are H&E stainings, bottom two cores are immunohistochemistry (detection of specific proteins in tissues using antibodies). RIGHT PANEL: Triple immunofluorescence-staining image of a developing breast tumor.

Until now, Thijs and the researchers at the Derksen Lab have discovered a molecular mechanism that explains how invasive breast cancer cells may stop dividing and linger in the body for years and what triggers expansion at the metastatic site. Now, they are probing how to target these “sleeping cells” during dissemination and stop the growing cells with therapeutics.

Discovery-based fundamental science is essential to establish the building blocks of therapeutic interventions. “We aim to bridge both aspects, understanding the molecular signalling and discovering or identifying the means to target them. Most importantly, we have the tools to test such in our clinical mouse models and all subtypes of invasive breast cancer. Being able to make these translational steps fast and efficient is a unique aspect of our work” says Thijs.

Thijs also supports the day-to-day supervision of bachelor, master and the Ph.D. students. He also teaches a variety of undergraduate classes at Utrecht University. Thijs also manages the clinical outsourcing and dissemination, including patient advocate involvement. Thijs also holds a leadership position within the COST Action Lobsterpot (CA19138), an initiative of the European Lobular Breast Cancer Consortium (www.elbcc.org).

According to Thijs, being a part of the Mechano·Control consortium is a thrill and a great opportunity to work with colleagues all over the world that work at very different scales. “A single email, text or conversation is sufficient to spark new ideas or endeavours. Combining all of our skills and thinking outside the box is exciting. Not only for your own development, but also to obtain new views on scientific problems. We have a collaborative spirit and were able to test a lot of hypotheses which otherwise would not have been tested.”

Cellular push and pull, a key to the body’s response to processes such as cancer

Researchers, led by Pere Roca-Cusachs at the Institute for Bioengineering of Catalonia (IBEC) discover how force dynamics affect cells, and living tissues. The results give an insight into the critical mechanical processes that occur in different diseases such as cancer.

From the vocal cords that produce our voice, to our heartbeat, our body’s cells are constantly subjected to mechanical forces that steadily change their response to these stimuli, regulating vital processes, in healthy individuals and in diseases such as cancer alike. Nevertheless, despite their importance, we remain largely ignorant of how cells sense and respond to these forces.

Isaac Almendros and Pere Roca-Cusachs (from left to right) leaders of the research.

Now, an international team co-led by the researcher Pere Roca-Cusachs, from the Institute for Bioengineering of Catalonia (IBEC), and Isaac Almendros, a researcher at the Respiratory Diseases Networking Biomedical Research Centre (CIBERES) and IDIBAPS, both professors at the Faculty of Medicine and Health Sciences of the University of Barcelona, has just proven that what determines mechanical sensitivity in cells is the rate at which the force is applied, in other words, how fast the force is applied. The paper has been published in the prestigious journalNature Communications and shows, for the first time in vivo, the predictions of the “molecular clutch” model.
These results will help, for example, to gain a better understanding of how a cancerous tumour proliferates, as well as how the heart, the vocal cords or the respiratory system respond to the constant variation of forces to which they are repeatedly exposed.  

A constant cellular “push and pull” 

The researchers observed that there are two responses to the force applied to a cell, using state-of-the-art techniques such as Atomic Force Microscopy (AFM) or so-called “optical tweezers”.  

On the one hand, the cytoskeleton, the dense network of fibres (mainly actin), which has, among others, the function of maintaining the shape and structure of the cell, is reinforced when the cell is subjected to a moderate force. In this regard, the cell is able to sense and respond to mechanical force, and the reinforcement of the cytoskeleton leads to a stiffening of the cell, and the localisation of the YAP protein in the nucleus. When this occurs, the YAP protein controls and activates genes related to cancer development.  

Rat lung responding to ventilation with YAP protein staining

On the other hand, if the rate of force applied is repeatedly applied above a certain value, a reverse effect occurs; the cell no longer senses the mechanical forces. In other words, instead of the cytoskeleton and the cell becoming more rigid, a partial breakdown of the cytoskeleton occurs, leading to a softening of the cell.  

Like stretching and shrinking chewing gum, we have subjected cells to different forces in a controlled and precise manner, and we have seen that the rate at which the force is applied is of the utmost importance in determining the cellular response. 

Ion Andreu (IBEC), co-lead author of the study. 

A model corroborated by in vivo experiments 

To understand how the reinforcement and softening effects of the cytoskeleton are related, the researchers developed a computational model that considers the effect of the progressive application of force on the cytoskeleton and the “couplings” (proteins involved in binding the cell to the substrate, such as talin and integrin). These “couplings” are somewhat akin to the effect of the clutch of a car, in tightening the mechanical connection between the engine and the wheels, which is why the model is known as the “molecular clutch”.  

Next, the scientists performed experiments on laboratory rats to prove that the results observed in single cells also occur in in-vivo whole organs. To do so, the researchers studied the lungs, which naturally undergo cyclical mechanical stretching during breathing. Specifically, the two lungs were ventilated at different rates, with one lung filling and emptying faster (hyperventilation) and the other more slowly, while maintaining a normal total ventilation rate.  

After analysing and comparing cells from both lungs, they observed that the YAP protein increased its nuclear localisation only in cells from the lung subjected to hyperventilation. This increase in YAP in in-vivo samples, caused by the “cellular tug-of-war”, was akin to that found in proliferating cancer tumours. 

Our results demonstrate, at organ level, the role of force application rate in the transduction of the ventilation-induced mechanical signal in the lungs.  

Bryan Falcones (IBEC-UB), co-lead author of the study

The paper sets out a mechanism by which cells respond, not only to direct forces, but also to other passive mechanical stimuli, such as the stiffness of the substrate on which they are located. The results give an insight into understanding how a priori opposite phenomena, such as reinforcing and softening of the cytoskeleton, can go hand in hand with controlling cell mechanics and respond specifically to different situations. 

Reference article:  Ion Andreu, Bryan Falcones, Sebastian Hurst, Nimesh Chahare, Xarxa Quiroga, Anabel-Lise Le Roux, Zanetta Kechagia, Amy E. M. Beedle, Alberto Elósegui-Artola, Xavier Trepat, Ramon Farré, Timo Betz, Isaac Almendros & Pere Roca-Cusachs. The force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening. Nature Communications, 2021. 

Original piece: IBEC

Project Stories: Interview with Marc Mora

Project Stories: Interview with Marc Mora

In order to understand and control how cells transmit and detect mechanical forces, it is important to take a look at every scale: from the nanometre level all the way up to entire organisms. The Mechano·Control project brings together an interdisciplinary research community with expertise in different scientific fields and scales. With this interview, we will take a closer look at the nanometre level, which is the level of molecules.

Cells stick to their surrounding extracellular matrix and to other cells using integrins and cadherins. Forces applied to these molecular links change their properties, determining how cells behave, and sometimes activating the expression of genes. Let’s travel to London together with Marc Mora, a Postdoc in Sergi Garcia-Manyes’ lab at King’s College London, and dive into the nano world.

The role of the Garcia-Manyes lab in London is to provide their expertise on single molecule techniques. More specifically, they aim to decipher how mechanical properties of proteins impact cellular processes, such as the molecular mechanisms of adhesion or the passage of proteins through the Nuclear Pore Complex (NPC). The NPC is a large complex of proteins, that spans the nuclear envelope, a double membrane that surrounds the nucleus in eukaryotic cells.

In the last couple of years, Marc Mora has been studying the nuclear translocation process of proteins through the NPC, which is a recently uncovered step in nuclear mechanotransduction. More specifically, Marc is investigating the interplay between two intrinsic properties of proteins, their mechanical stability and protein mass, to understand and predict the rate of nuclear shuttling of proteins, and in particular, of key mechanosensitive transcription factors such as the oncogenic YAP and MRTF-A, known for playing a key role in cancer progression. But how do researchers work in the lab at this very tiny scale?

Marc Mora “Exploring how the nanomechanical properties of proteins affect their nuclear translocation in cells”

Concretely, Marc performs cellular experiments where he in cancer cell lines (such as U2OS and MDA-MB-231) with previously characterised mechanical properties, which they independently measure during in vitro experiments with single molecule techniques. These protein cargoes with varying mechanical stabilities are manipulated in and out of the nucleus using optogenetic methods involving blue light illumination. In parallel to these experiments, Marc also uses single molecule magnetic tweezers to study the conformational dynamics under low physiological forces of key protein mechanosensors, such as talin, that play a fundamental role in determining the adhesion of several cancer cell lines.

Single Molecule Magnetic tweezer

With all these experiments, Marc and the team at KCL aim to uncover whether the mechanical properties of individual proteins have a direct, knock-on effect at the cellular level.

“We believe we will be able to build a comprehensive model that integrates protein mass, protein sequence and mechanical stability to understand the dynamics of proteins, such as mechanosensensitive transcription factors, as they shuttle to and away from the nucleus.”

Marc Mora, KCL

And this is crucial for the Mechano·Control ultimate goal. If the researchers manage to further understand the impact of protein mechanics on cellular behaviour, they will be able to target specific adhesive interactions at the cellular level and determine new steps in controlling the nuclear mechanotransduction of key oncogenic transcription factors, with the final future goal of abrogating breast tumour progression. By understanding these processes with sub-molecular detail, we will use the control of protein elasticity as new therapeutic tools to fight breast cancer treatment.

“I feel very lucky to have the opportunity to be part of this European Project where scientists form different fields come together to work towards a common goal. It is very important for my academic development to have the opportunity of being part of such project, aiming to create such impact on people’s lives” adds Marc Mora. As we mentioned before, the Mechano·Control project covers a wide variety of scientific disciplines at very different scales, and as Marc says “This provides the grounds to put our single molecule work into a much broader context. This is an eye-opening experience in many different levels.”

Researchers discover how the intestinal epithelium folds and moves by measuring its forces

Researchers discover how the intestinal epithelium folds and moves by measuring its forces

An international team led by Xavier Trepat at IBEC, with support from “La Caixa Foundation, measures the cellular forces in mini-intestines grown in the laboratory, deciphering how the inner wall of this vital organ folds and moves. The study, published in Nature Cell Biology, opens the doors to a better understanding of the bases of diseases such as celiac disease or cancer, and to the ability to find solutions for gut diseases through the development of new therapies.

Intestine cross section showing its characteristic folded structure. Credit: Amy Engevik

The human intestine is made up of more than 40 square meters of tissue, with a multitude of folds on its internal surface that resemble valleys and mountain peaks in order to increase the absorption of nutrients. The intestine also has the unique characteristic of being in a continuous state of self-renewal. This means that approximately every 5 days all the cells of its inner walls are renewed to guarantee correct intestinal function. Until now, scientists knew that this renewal could take place thanks to stem cells, which are protected in the so-called intestinal crypts, and which give rise to new differentiated cells. However, the process that leads to the concave shape of the crypts and the migration of new cells towards the intestinal peaks was unknown.  

Now, an international team led by Xavier Trepat, ICREA Research Professor and Group Leader at IBEC, in collaboration with the IRB, researchers from the UB and UPC universities in Barcelona, and the Curie Institute of Paris, has deciphered the mechanisms leading the crypts to adopt and maintain their concave shape, and how the migration movement of the cells towards the peaks occurs, without the intestine losing its characteristic folded shape. The study, published in the prestigious journal Nature Cell Biology, has combined computer modelling, led by Marino Arroyo, professor at the UPC, researcher associated with IBEC and member of CIMNE, with experiments with intestinal organoids from mouse cells, and shows that this process is possible thanks to the mechanical forces exerted by the cells. An important part of this study has been supported by the “la Caixa” Foundation within the framework of the CaixaResearch programme. The entity has also awarded a scholarship to the first co-author, Gerardo Ceada, to carry out his PhD at IBEC.

The forces determine and control the shape of the intestine and the movement of the cells

Using mouse stem cells and bioengineering and mechanobiology techniques, researchers have developed mini-intestines, organoids that resemble the three-dimensional structure of peaks and valleys, recapitulating tissue functions in vivo. Using microscopy technologies developed by the same group, researchers carried out high-resolution experiments for the first time that have allowed them to obtain 3D maps showing the forces exerted by each cell. 

In addition, with this in vitro model, scientists have shown that the movement of new cells to the peak is also controlled by mechanical forces exerted by the cells themselves, specifically by the cytoskeleton, a network of filaments that determines and maintains cell shape. 

Contrary to what was believed up until now, we have been able to determine that it is not the cells of the intestinal crypt that push the new ones up, but that it is the cells at the peak pulling the new ones up, akin to a mountaineer who helps another climber by pulling them up.

Gerardo Ceada (IBEC) 

With this system, we have discovered that the crypt is concave because the cells have more tension on their upper surface than on the bottom, which causes them to adopt a conical shape. When this occurs in several cells next to each other, the result is that the tissue folds, giving rise to a pattern of peaks and valleys.

Carlos Pérez-González, (IBEC and Curie Institute)

The new mini-intestine model will allow further studies of diseases such as cancer, celiac disease or colitis to be conducted in reproducible and real conditions, in which there is an uncontrolled proliferation of stem cells or a destructuring of the folds. In addition, intestinal organoids can be manufactured with human cells and used for the development of new drugs or for the study of the intestinal microbiota.  

Reference article:  C. Pérez-González, G. Ceada, F. Greco, M. Matejčić, M. Gómez-González, N. Castro, A. Menendez, S. Kale, D. Krndija, A. G. Clark, V. Ram Gannavarapu, A. Álvarez-Varela, P. Roca-Cusachs, E. Batlle, D. Matic Vignjevic, M. Arroyo and X. Trepat. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration. Nature Cell Biology, 2021.