New Cancer Research – Converting Cancer Cells to Fat Cells to Stop Cancer’s Spread

A method for fooling breast cancer cells into fat cells has been discovered by researchers from the University of Basel.

The team were able to transform EMT-derived breast cancer cells into fat cells in a mouse model of the disease – preventing the formation of metastases. The proof-of-concept study was published in the journal Cancer Cell. 

Malignant cells can rapidly respond and adapt to changing microenvironmental conditions, by reactivating a cellular process called epithelial-mesenchymal transition (EMT), enabling them to alter their molecular properties and transdifferentiate into a different type of cell (cellular plasticity).

Senior author of the study Gerhard Christofori, professor of biochemistry at the University of Basel, commented in a recent press release: “The breast cancer cells that underwent an EMT not only differentiated into fat cells, but also completely stopped proliferating.”

“As far as we can tell from long-term culture experiments, the cancer cells-turned-fat cells remain fat cells and do not revert back to breast cancer cells,” he explained.

Epithelial-mesenchymal transition and cancer 

Cancer cells can exploit EMT – a process that is usually associated with the development of organs during embryogenesis – in order to migrate away from the primary tumor and form secondary metastases. Cellular plasticity is linked to cancer survival, invasion, tumor heterogeneity and resistance to both chemo and targeted therapies. In addition, EMT and the inverse process termed mesenchymal-epithelial transition (MET) both play a role in a cancer cell’s ability to metastasize.

Using mouse models of both murine and human breast cancer the team investigated whether they could therapeutically target cancer cells during the process of EMT – whilst the cells are in a highly plastic state. When the mice were administered Rosiglitazone in combination with MEK inhibitors it provoked the transformation of the cancer cells into post-mitotic and functional adipocytes (fat cells). In addition, primary tumor growth was suppressed and metastasis was prevented. 

Cancer cells marked in green and a fat cell marked in red on the surface of a tumor (left). After treatment (right), three former cancer cells have been converted into fat cells. The combined marking in green and red causes them to appear dark yellow. Credit: University of Basel, Department of Biomedicine

Christofori highlights the two major findings in the study: 

“Firstly, we demonstrate that breast cancer cells that undergo an EMT and thus become malignant, metastatic and therapy-resistant, exhibit a high degree of stemness, also referred to as plasticity. It is thus possible to convert these malignant cells into other cell types, as shown here by a conversion to adipocytes.”

“Secondly, the conversion of malignant breast cancer cells into adipocytes not only changes their differentiation status but also represses their invasive properties and thus metastasis formation and their proliferation. Note that adipocytes do not proliferate anymore, they are called ‘post-mitotic’, hence the therapeutic effect.”

Since both drugs used in the preclinical study were FDA-approved the team are hopeful that it may be possible to translate this therapeutic approach to the clinic. 

“Since in patients this approach could only be tested in combination with conventional chemotherapy, the next steps will be to assess in mouse models of breast cancer whether and how this trans-differentiation therapy approach synergizes with conventional chemotherapy. In addition, we will test whether the approach is also applicable to other cancer types. These studies will be continued in our laboratories in the near future.”

Journal Reference: Ronen et al. Gain Fat–Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis. Cancer Cell. (2019). Available at: https://www.cell.com/cancer-cell/fulltext/S1535-6108(18)30573-7 

Gerhard Christofori was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks

Researchers show that electrons in graphene can be moved along a predefined path

Physicists at the University of Basel have shown for the first time that electrons in graphene can be moved along a predefined path. This movement occurs entirely without loss and could provide a basis for numerous applications in the field of electronics. The research group led by Professor Christian Schönenberger at the Swiss Nanoscience Institute and the Department of Physics at the University of Basel is publishing its results together with European colleagues in the renowned scientific journal Nature Communications (“Snake trajectories in ultraclean graphene p–n junctions”).

The principle of the experiment: The honeycomb grid provides an atomic graphene layer stretched between two electrical contacts (silver). The lower area contains two control electrodes (gold), which are used to generate an electrical field. A magnetic field is also applied vertically to the graphene level. Combining an electrical field and a magnetic field means that the electrons move along a snake state.

For some years, the research group led by Professor Christian Schönenberger at the Swiss Nanoscience Institute and the Department of Physics has been looking at graphene, the “miracle material”. Scientists at the University of Basel have developed methods that allow them to stretch, examine and manipulate layers of pure graphene. In doing so, they discovered that electrons can move in this pure graphene practically undisturbed – similar to rays of light. To lead the electrons from one specific place to another, they planned to actively guide the electrons along a predefined path in the material.

Electrical and magnetic fields combined

For the first time, the scientists in Basel have succeeded in switching the guidance of the electrons on and off and guiding them without any loss. The mechanism applied is based on a property that occurs only in graphene. Combining an electrical field and a magnetic field means that the electrons move along a snake state. The line bends to the right, then to the left. This switch is due to the sequence of positive and negative mass – a phenomenon that can only be realized in graphene and could be used as a novel switch.

“A nano-switch of this type in graphene can be incorporated into a wide variety of devices and operated simply by altering the magnetic field or the electrical field,” comments Professor Christian Schönenberger on the latest results from his group. Teams of physicists from Regensburg, Budapest and Grenoble were also involved in the study published in Nature Communications.

Material with special properties

Graphene is a very special material with promising properties. It is made up of a single layer of carbon atoms but is still very mechanically durable and resistant. Its excellent electrical conductivity in particular makes graphene the subject of research by numerous teams of scientists around the world.

The particular properties of this material were examined theoretically several decades ago. However, it was not until 2004 that physicists Andre Geim and Kostya Novoselov succeeded in producing graphene for experimental tests. The two researchers used scotch tape to peel away individual two-dimensional graphene layers from the original material, graphite. They received the 2010 Nobel Prize for Physics for this seemingly simple method, which enabled experimental graphene research for the first time. Since then, researchers worldwide have perfected the production process with tremendous speed.

Source: Universität Basel

Using Nanotechnology Against Malaria Parasites

Malaria parasites invade human red blood cells, they then disrupt them and infect others. Researchers at the University of Basel and the Swiss Tropical and Public Health Institute have now developed so-called nanomimics of host cell membranes that trick the parasites. This could lead to novel treatment and vaccination strategies in the fight against malaria and other infectious diseases. Their research results have been published in the scientific journal ACS Nano.

For many infectious diseases no vaccine currently exists. In addition, resistance against currently used drugs is spreading rapidly. To fight these diseases, innovative strategies using new mechanisms of action are needed. The malaria parasite Plasmodium falciparum that is transmitted by the Anopheles mosquito is such an example. Malaria is still responsible for more than 600,000 deaths annually, especially affecting children in Africa (WHO, 2012).

Artificial bubbles with receptors

Malaria parasites normally invade human red blood cells in which they hide and reproduce. They then make the host cell burst and infect new cells. Using nanomimics, this cycle can now be effectively disrupted: The egressing parasites now bind to the nanomimics instead of the red blood cells.

Researchers of groups led by Prof. Wolfgang Meier, Prof. Cornelia Palivan (both at the University of Basel) and Prof. Hans-Peter Beck (Swiss TPH) have successfully designed and tested host cell nanomimics. For this, they developed a simple procedure to produce polymer vesicles – small artificial bubbles – with host cell receptors on the surface. The preparation of such polymer vesicles with water-soluble host receptors was done by using a mixture of two different block copolymers. In aqueous solution, the nanomimics spontaneously form by self-assembly.

Blocking parasites efficiently

Usually, the malaria parasites destroy their host cells after 48 hours and then infect new red blood cells. At this stage, they have to bind specific host cell receptors. Nanomimics are now able to bind the egressing parasites, thus blocking the invasion of new cells. The parasites are no longer able to invade host cells, however, they are fully accessible to the immune system.

The researchers examined the interaction of nanomimics with malaria parasites in detail by using fluorescence and electron microscopy. A large number of nanomimics were able to bind to the parasites and the reduction of infection through the nanomimics was 100-fold higher when compared to a soluble form of the host cell receptors. In other words: In order to block all parasites, a 100 times higher concentration of soluble host cell receptors is needed, than when the receptors are presented on the surface of nanomimics.

“Our results could lead to new alternative treatment and vaccines strategies in the future”, says Adrian Najer first-author of the study. Since many other pathogens use the same host cell receptor for invasion, the nanomimics might also be used against other infectious diseases. The research project was funded by the Swiss National Science Foundation and the NCCR “Molecular Systems Engineering”.

Explore further: Why humans don’t suffer from chimpanzee malaria

More information: Adrian Najer, Dalin Wu, Andrej Bieri, Françoise Brand, Cornelia G. Palivan, Hans-Peter Beck, and Wolfgang Meier. “Nanomimics of Host Cell Membranes Block Invasion and Expose Invasive Malaria Parasites.” ACS Nano, Publication Date (Web): November 29, 2014 | DOI: 10.1021/nn5054206

Journal reference: ACS Nano

The nanomechanical signature of breast cancer

 

 

 

 

 

 

Using ARTIDIS to feel the tissue structure of a tumor biopsy by a nanometer-sized atomic force microscope tip. Image: Martin Oeggerli

The spread of cancer cells from primary tumors to other parts of the body remains the leading cause of cancer-related deaths. The research groups of Roderick Lim and Cora-Ann Schoenenberger from the Biozentrum of the University of Basel, reveal in the journal Nature Nanotechnology how the unique nanomechanical properties of breast cancer cells are fundamental to the process of metastasis. The discovery of specific breast cancer “fingerprints” was made using breakthrough nanotechnology known as ARTIDIS. Lim’s team has now been awarded about 1.2 million Swiss francs from the Commission for Technology and Innovation (CTI) to further develop ARTIDIS.
Breast cancer is the most common form of cancer in women with 5,500 patients being diagnosed with the disease in Switzerland each year. Despite major scientific advancements in our understanding of the disease, breast cancer diagnostics remains slow and subjective. Here, the real danger lies in the lack of knowing whether metastasis, the spread of cancer, has already occurred. Nevertheless, important clues may be hidden in how metastasis is linked to specific structural alterations in both cancer cells and the surrounding extracellular matrix. This forms the motivation behind ARTIDIS (“Automated and Reliable Tissue Diagnostics”), which was conceived by Dr. med. Marko Loparic, Dr. Marija Plodinec and Prof. Roderick Lim to measure the local nanomechanical properties of tissue biopsies.

“Fingerprinting” breast tumors
At the heart of ARTIDIS lies an ultra-sharp atomic force microscope tip of several nanometers in size that is used as a local mechanical probe to “feel” the cells and extracellular structures within a tumor biopsy. In this way, a nanomechanical “fingerprint” of the tissue is obtained by systematically acquiring tens of thousands of force measurements over an entire biopsy.

Subsequent analysis of over one hundred patient biopsies could confirm that the fingerprint of malignant breast tumors is markedly different as compared to healthy tissue and benign tumors. This was validated by histological analyses carried out by clinicians at the University Hospital Basel, which showed a complete agreement with ARTIDIS. Moreover, the same nanomechanical fingerprints were found in animal studies initiated at the Friedrich Miescher Institute.

Plodinec, first author of the study, explains: “This unique fingerprint reflects the heterogeneous make-up of malignant tissue whereas healthy tissue and benign tumors are more homogenous.” Strikingly, malignant tissue also featured a marked predominance of “soft” regions that is a characteristic of cancer cells and the altered microenvironment at the tumor core. The significance of these findings lies in reconciling the notion that soft cancer cells can more easily deform and “squeeze” through their surroundings. Indeed, the presence of the same type of “soft” phenotype in secondary lung tumors of mice reinforces the close correlation between the physical properties of cancer cells and their metastatic potential.

ARTIDIS in the clinics
“Resolving such basic scientific aspects of cancer further underscores the use of nanomechanical fingerprints as quantitative markers for cancer diagnostics with the potential to prognose metastasis,” states Loparic, who is project manager for ARTIDIS. On an important practical note, a complete biopsy analysis by ARTIDIS currently takes four hours in comparison to conventional diagnostics, which can take one week. Based on the potential societal impact of ARTIDIS to revolutionize breast cancer diagnostics, Lim’s team and the Swiss company Nanosurf AG have now been awarded about 1.2 million Swiss francs by the Commission for Technology and Innovation (CTI) to further develop ARTIDIS into a state-of-the-art device for disease diagnostics with further applications in nanomedicine.

Over the next two years, Lim and colleagues will engage and work closely with clinicians to develop ARTIDIS into an easy-to-use “push-button” application to fingerprint diseases across a wide range of biological tissues. As a historical starting point, the first ARTIDIS demo-lab has already been established at the University Hospital Eye Clinic to collect data on retinal diseases with the goal of improving treatment strategies.

The nanomechanical signature of breast cancer

Source: University of Basel