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:
“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
A Time To Heal
Researchers from Imperial College London have created a new molecule that can “talk” to the cells in the area near injured tissues to encourage wound healing.
“This intelligent healing is useful during every phase of the healing process, has the potential to increase the body’s chance to recover, and has far-reaching uses on many different types of wounds,” lead researcher Ben Almquist said in a news release.
Setting A TrAP
The Imperial team describes the wound-healing molecules, which it calls traction force-activated payloads (TrAPs), in a study published Monday in the journal Advanced Materials.
The first step to creating TrAPs was folding segments of DNA into aptamers, which are three-dimensional shapes that latch tightly to proteins. The researchers then added a “handle” to one end of the aptamer.
As cells navigated the area near a wound during lab testing, they would pull on this handle, causing the aptamer to open and release proteins that encouraged wound healing. By changing the handle, the researchers found they could control which cells activated the TrAPs.
According to Almquist, “TrAPs provide a flexible method of actively communicating with wounds, as well as key instructions when and where they are needed.”
To The Clinic
It can take a long time for research to move from the laboratory to the clinical trial stage, but the TrAPs team might be able to speed along the path. That’s because aptamers are already used for drug delivery, meaning they’re already considered safe for human use.
TrAPs are also fairly straightforward to create, meaning it wouldn’t be difficult to scale the technology to industrial levels. According to the researchers’ paper, doctors could then deliver the TrAPs via anything from collagen sponges to polyacrylamide gels. So if future testing goes well, the molecules could soon change how we heal a variety of wounds.
READ MORE: New Material Could ‘Drive Wound Healing’ Using the Body’s Inbuilt Healing System [Imperial College London]
More on aptamers: New Nanobots Kill Cancerous Tumors by Cutting off Their Blood Supply
In 2016, Craig Venter and his team at Synthetic Genomics announced that they had created a lifeform called JCVI-syn3.0, whose genome consisted of only 473 genes.
This stripped-down organism was a significant breakthrough in the development of artificial life as it enabled us to understand more fully what individual genes do. (In the case of JCVI-syn3.0, most of them were used to create RNA and proteins, preserve genetic fidelity during reproduction and create the cell membrane.
The functions of about a third remain a mystery.)
Venter’s achievement followed an earlier breakthrough in 2014, when Floyd Romesberg at Romesberg Lab in California succeeded in creating xeno nucleic acid (XNA), a synthetic alternative to DNA, using amino acids not found among the naturally occurring four nucleotides: adenine, cytosine, guanine and thymine.
And, most recently we have seen huge advances in the use of CRISPR, a gene-editing tool that allows substitution or injection of DNA sequences at chosen locations in a genome.
Together, these developments mean that in 2019 we will have to take seriously the possibility of our developing multicellular artificial life, and we will need to start thinking about the ethical and philosophical challenges such a possibility brings up.
In the near future we can reasonably anticipate that a large number of unnatural single-cell life forms will be created using artificially edited genomes to correct for genetic defects or to add new features to an organism’s phenotype.
It is already possible to design bacterial forms, for example, that can metabolise pollutants or produce particular substances.
We can also anticipate that new life forms may be created that have never existed in nature through the use of conventional and perhaps artificially arranged codons (nucleotide sequences that manage protein synthesis).
These are likely to make use of the conventional machinery of mitotic cell reproduction and of conventional ribosomes, creating proteins through RNA or XNA interpretation.
And there will be increasing pressures to continue this research. We may need to accelerate the evolution of terrestrial life forms, for example, including homo sapiens, so that they carry traits and capabilities needed for life in space or even on our own changing planet.
All of this will bring up serious issues as to how we see ourselves – and behave – as a species.
While the creation of multicellular organisms that are capable of sexual reproduction is still a long way off, in 2019 we will need to begin a serious debate about whether artificially evolved humans are our future, and if we should put an end to these experiments before it is too late.
Vint Cerf of ‘Wired’
Scientists from Jülich together with colleagues from Aachen and Turin have produced a memristive element made from nanowires that functions in much the same way as a biological nerve cell.
The component is able to save and process information, as well as receive numerous signals in parallel. The resistive switching cell made from oxide crystal nanowires is thus an ideal candidate for use in building bioinspired “neuromorphic” processors, able to take over the diverse functions of biological synapses and neurons.
Systems with neuromorphic chips that imitate the way the human brain works offer significant advantages. These types of computers work in a decentralised way, having at their disposal a multitude of processors, which, like neurons in the brain, are connected to each other by networks. If a processor breaks down, another can take over its function.
What is more, just like in the brain, where practice leads to improved signal transfer, a bioinspired processor should have the capacity to learn.
“With today’s semiconductor technology, these functions are to some extent already achievable. These systems are, however, suitable for particular applications and require a lot of space and energy,” says Dr. Ilia Valov from Forschungszentrum Jülich. “Our nanowire devices made from zinc oxide crystals can inherently process and even store information, and are extremely small and energy efficient.”
For years, memristive cells have been ascribed the best chances of taking over the function of neurons and synapses in bioinspired computers. They alter their electrical resistance depending on the intensity and direction of the electric current flowing through them.
In contrast to conventional transistors, their last resistance value remains intact even when the electric current is switched off. Memristors are thus fundamentally capable of learning.
In order to create these properties, scientists at Forschungszentrum Jülich and RWTH Aachen University used a single zinc oxide nanowire, produced by their colleagues from the polytechnic university in Turin. Measuring approximately one 10,000th of a millimeter in size, this type of nanowire is over 1,000 times thinner than a human hair. The resulting memristive component not only takes up a tiny amount of space, but is also able to switch much faster than flash memory.
Nanowires offer promising novel physical properties compared to other solids and are used among other things in the development of new types of solar cells, sensors, batteries and computer chips. Their manufacture is comparatively simple. Nanowires result from the evaporation deposition of specified materials onto a suitable substrate, where they practically grow of their own accord.
In order to create a functioning cell, both ends of the nanowire must be attached to suitable metals, in this case platinum and silver. The metals function as electrodes, and in addition, release ions triggered by an appropriate electric current. The metal ions are able to spread over the surface of the wire and build a bridge to alter its conductivity.
Components made from single nanowiresare, however, still too isolated to be of practical use in chips. Consequently, the next step being planned by the Jülich and Turin researchers is to produce and study a memristive element, composed of a larger, relatively easy to generate group of several hundred nanowires offering more exciting functionalities.
Provided by Forschungszentrum Juelich
Explore further: Scientists create a prototype neural network based on memristors
Researchers from the University of Queensland’s Australian Institute for Bioengineering and Nanotechnology (AIBN) have discovered a unique nano-scaled DNA signature that appears to be common to all cancers.
The study, which was supported by a grant from the National Breast Cancer Foundation and is published in the journal Nature Communications, reveals new insight about how epigenetic reprogramming in cancer regulates the physical and chemical properties of DNA and could lead to an entirely new approach to point-of-care diagnostics.
“Because cancer is an extremely complicated and variable disease, it has been difficult to find a simple signature common to all cancers, yet distinct from healthy cells,” explains AIBN researcher Dr. Abu Sina.
To address this, Dr. Sina and Dr. Laura Carrascosa, who are working with Professor Matt Trau at AIBN, focussed on something called circulating free DNA.
Like healthy cells, cancer cells are always in the process of dying and renewing. When they die, they essentially explode and release their cargo, including DNA, which then circulates.
“There’s been a big hunt to find whether there is some distinct DNA signature that is just in the cancer and not in the rest of the body,” says Dr. Carrascosa.
So they examined epigenetic patterns on the genomes of cancer cells and healthy cells. In other words, they looked for patterns of molecules, called methyl groups, which decorate the DNA. These methyl groups are important to cell function because they serve as signals that control which genes are turned on and off at any given time.
In healthy cells, these methyl groups are spread out across the genome. However, the AIBN team discovered that the genome of a cancer cell is essentially barren except for intense clusters of methyl groups at very specific locations.
This unique signature—which they dubbed the cancer “methylscape”, for methylation landscape—appeared in every type of breast cancer they examined and appeared in other forms of cancer, too, including prostate cancer, colorectal cancer and lymphoma.
“Virtually every piece of cancerous DNA we examined had this highly predictable pattern,” says Professor Trau.
He says that if you think of a cell as a hard-drive, then the new findings suggest that cancer needs certain genetic programmes or apps in order to run.
“It seems to be a general feature for all cancer,” he says. “It’s a startling discovery.”
They also discovered that, when placed in solution, those intense clusters of methyl groups cause cancer DNA fragments to fold up into three-dimensional nanostructures that really like to stick to gold.
Taking advantage of this, the researchers designed an assay which uses gold nanoparticles that instantly change colour depending on whether or not these 3-D nanostructures of cancer DNA are present.
“This happens in one drop of fluid,” says Trau. “You can detect it by eye, it’s as simple as that.”
The technology has also been adapted for electrochemical systems, which allows inexpensive and portable detection that could eventually be performed using a mobile phone.
So far they’ve tested the new technology on 200 samples across different types of human cancers, and healthy cells. In some cases, the accuracy of cancer detection runs as high as 90%.
“It works for tissue derived genomic DNA and blood derived circulating free DNA,” says Sina. “This new discovery could be a game-changer in the field of point of care cancer diagnostics.” It’s not perfect yet, but it’s a promising start and will only get better with time, says the team.
“We certainly don’t know yet whether it’s the Holy Grail or not for all cancer diagnostics,” says Trau, “but it looks really interesting as an incredibly simple universal marker of cancer, and as a very accessible and inexpensive technology that does not require complicated lab based equipment like DNA sequencing.”
More information: Abu Ali Ibn Sina et al, Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker, Nature Communications(2018). DOI: 10.1038/s41467-018-07214-w
Provided by University of Queensland
Explore further: New cancer monitoring technology worth its weight in gold
Genetic diseases may soon be a thing of the past thanks to nanotechnology, which employs tiny particles to manipulate cells and change our DNA.
Here is how cancer treatment often runs today: a patient develops an aggressive tumor. A surgeon operates to remove the tumor, but a few cancer cells remain, hiding in the body. Chemotherapy is administered, weakening both patient and cancer cells. But the cancer does not die; it comes back and eventually kills the patient.
Now imagine another scenario. After surgery, strands of DNA anchored in tiny gold particles are injected into the affected area. The DNA strands bind to the tumor cells, killing them directly, without the help of chemo. The healthy cells around the tumor cells, which don’t express the tumor gene, are untouched.
Just like that, all the tumor cell stragglers are rendered harmless, corrected on the genetic level. The patient is cured, and without having to endure months of chemotherapy and its brutal side effects: hair loss, nausea and extreme weakness.
The future of medicine won’t focus on treating the symptoms of a disease, according to reseachers: it will focus on curing it at the genetic level.
Nanotechnology, the science of working with particles that are one billionth of a meter, is enabling scientists to change gene expression on the cellular level, potentially curing a host of diseases.
“Nanotechnology medical developments over the coming years will have a wide variety of uses and could potentially save a great number of lives,” says Eleonore Pauwels, senior associate and scholar at the Wilson Center, an interdisciplinary policy research center.
The science of using nanoparticles got its start with a lecture by theoretical physicist Richard Feynman in 1959, but because of the technical challenges, it is only in the past 10 years or so that the technology has really taken off for practical medical applications.
Figuring out how to consistently create the right nanoparticle, get it into the right tissue, ensure it is not degraded and does what it was programmed to do, took some time.
The science of nanotechnology depends on the fact that when things get super small, they function differently. Protein, for example, is a naturally occurring nanoparticle. A single protein molecule is a very different entity than a human being, which is made up of many protein molecules.
Gold, which is used often in medicine, is red when broken down into tiny particles. That microscopic bright red color has been used for centuries to give red stained glass its color.
“Because of their small size, engineered nanomaterials have unique properties that do not exist at the larger scale: increased surface area, charge, reactivity and other physicochemical properties, all of which may affect how nanomaterials interact with biological entities, like cells,” says Sara Brenner, assistant professor of nanobioscience at SUNY Polytechnic Institute.
Scientists are learning to take advantage of those properties to create new treatments. One of the most powerful examples uses DNA, says Chad Mirkin, a professor at Northwestern University and director of the International Institute for Nanotechnology.
DNA is rod shaped and normally would not be able to enter cells, which have developed protection against entry from foreign DNA segments.
But by using nanotechnology, many little snippets of DNA can be attached to a tiny, round synthetic core. The receptors on cells that would block rod shaped DNA do not recognize the tiny spheres of DNA and allow it to enter.
Using that property, a whole new class of treatments for genetic diseases is being developed.
By being able to insert DNA into existing cells, scientists can “attack disease at its genetic root and turn off receptors that regulate how a cell functions, stopping a disease pathway in its tracks,” explains Mirkin.
Right now, most of the research into developing therapies using spheres of DNA is focused on disease of the liver, says Mirkin, as anything a person takes in is going to be processed in the liver. Another area of research into nanotech treatments is the skin, as the treatment can be applied topically, making it easy to target one area.
“Potential applications are virtually endless,” explains Brenner. “But some areas of investigation right now for gene therapy are cancer, diabetes, AIDS, cystic fibrosis and heart disease.”
As research into using nanoparticles advances, scientists hope to be able to not just turn off specific signals in cells, but also eventually insert genes to correct for defects and cure more complex diseases.
Called gene therapy, it would involve inserting larger fragments of DNA into cells that have faulty DNA. For example, cystic fibrosis is caused by a defective gene called CFTR. If scientists can figure out a way to get a non-defective copy of the gene into the cells and correct it, they could cure the disease.
“Approximately 4,000 diseases have been found to have a genetic component and are therefore potential targets for gene therapy,” according to Brenner.
While nanotechnology has the potential to revolutionize medicine and how we view treatment of diseases, there are still kinks to work out.
Some of the challenges with nanotechnology include how to get nanoparticles into the right cells and tissues, and how to get them into the cells safely without the nanoparticles degrading.
Nanotechnology is still in its infancy, however. It’s only recently that we were able to produce microscopes that allowed us to see and manipulate nanoparticles.
Research requires bringing together a number of disciplines like chemistry, biomedical engineering, biology and physics. But pharmaceutical companies have already begun work on creating treatments using nanotech, and many are in various stages of development now. “It’s not a pipe dream,” says Mirkin. Being able to cure genetic diseases of all kinds is on the horizon.
IMMORTAL: Human beings could soon live forever
Dr Ian Pearson has previously said people will have the ability to “not die” by 2050 – just over 30 years from now.
Two of the methods he said humans might use were “body part renewal” and linking bodies with machines so that people are living their lives through an android.
But after Dr Pearson’s predictions, immortality may now be a step nearer following the launch of a new start-up.
Human is hoping to make the immortality dream a reality with an ambitious plan.
Last year, UK-based stem cell bank StemProject said it could eventually potentially develop treatments that allow humans to live until 200.
Watch Dr. Ian Pearson Talk About the Possibility of Immortality by 2050
A £10 million interdisciplinary collaboration is to target the most challenging of cancers using nanomedicine.
“We are going to pierce through the body’s natural barriers and deliver anti-cancer drugs to the heart of the tumour.” – George Malliaras
While the survival rate for most cancers has doubled over the past 40 years, some cancers such as those of the pancreas, brain, lung and oesophagus still have low survival rates.
Such cancers are now the target of an Interdisciplinary Research Collaboration (IRC) led by the University of Cambridge and involving researchers from Imperial College London, University College London and the Universities of Glasgow and Birmingham.
“Some cancers are difficult to remove by surgery and highly invasive, and they are also hard to treat because drugs often cannot reach them at high enough concentration,” explains George Malliaras, Prince Philip Professor of Technology in Cambridge’s Department of Engineering, who leads the IRC. “Pancreatic tumour cells, for instance, are protected by dense stromal tissue, and tumours of the central nervous system by the blood-brain barrier.”
The aim of the project, which is funded for six years by the Engineering and Physical Sciences Research Council, is to develop an array of new delivery technologies that can deliver almost any drug to any tumour in a large enough concentration to kill the cancerous cells.
Chemists, engineers, material scientists and pharmacologists will focus on developing particles, injectable gels and implantable devices to deliver the drugs. Cancer scientists and clinicians from the Cancer Research UK Cambridge Centre and partner sites will devise and carry out clinical trials. Experts in innovative manufacturing technologies will ensure the devices are able to be manufactured and robust enough to withstand surgical manipulation.
One technology the team will examine is the ability of advanced materials to self-assemble and entrap drugs inside metal-organic frameworks. These structures can carry enormous amounts of drugs, and be tuned both to target the tumour and to release the drug at an optimal rate.
“We are going to pierce through the body’s natural barriers,” says Malliaras, “and deliver anti-cancer drugs to the heart of the tumour.”
Dr Su Metcalfe, a member of George Malliaras’s team and who is already using NanoBioMed to treat Multuple Sclerosis, added “the power of nanotechnology to synergise with potent anti-cancer drugs will be profound and the award will speed delivery to patients.”
Nanotechnology brings a lot to the medical field, and a specific branch known as nanomedicine has evolved because of the growing interest in this area.
Drug delivery systems derived from materials (or particles) at the nano-level provide a way for drugs, that might otherwise be toxic to the body, to reach their intended target through encapsulation or conjugation approaches.
There are some issues which need to be ironed out, with respect to the size of some of these carriers against the regulatory definitions, but it is an area that is expanding drug delivery approaches beyond what was previously possible with conventional approaches.
Inorganic nanocarriers were the first type of nanotechnology-based drug delivery system to be trialled, yet their use and research is becoming less and less frequent. Many types of inorganic nanoparticle have been tried and tested, from gold, to iron oxide, to calcium phosphate, and beyond. Many inorganic nanoparticles are not biocompatible within the body, however, this can be overcome by functionalising the surface with organic molecules, such as PEG, to increase their compatibility within the body.
However, where this area has been let down is in their inability to be easily broken down after use and the subsequent difficulty to be excreted.
Organic-based nanocarriers are the fastest growing area of nano-inspired drug delivery systems, and the reason for this expansion is due to the (often) inability of inorganic drug carriers to be broken down within the body and excreted. By comparison, the organic make-up of organic carriers, such as those made of certain types of polymers, dendrimer architectures and lipid-based encapsulating vessels (liposomes), can be broken down and excreted and offer a much greater degree of biocompatibility.
Each mechanism of delivery is different for these systems. For example, dendrimer-based delivery vessels will often have the drug covalently linked (conjugated) to the dendrimer backbone itself, and when it reaches a target of interest, certain functional groups at the edges will bind to the target and release the drug through molecular cleavage.
However, the most common way of delivering drugs is through encapsulation, as the toxicity (and the possibility of the drug interacting with the body before it reaches the target) is significantly reduced.
By using this approach, the nanocarrier can uptake the drug of interest into its core, where it is only released once the nanocarrier has reached the target of interest—thus lowering the risk of the drug being cleaved and released on route to the target site.
Solid Drug Nanoparticles
Solid drug nanoparticles are another growing nanotechnology-inspired drug delivery system, but their use is not (yet) as widespread as organic delivery vessels. However, they do avoid some of the regulatory complications, as their use does not involve any extra species other than already approved drugs in an efficient nanoparticle form.
Solid drug nanoparticles are the nanoparticle form of a conventional drug; and take the form of being packed into a template, or as a suspension—therefore no delivery system is required and are administered by injection. The drug nanoparticles are often created through a bottom-up controlled precipitation of the drug to be administered, or by a top-down grinding approach of larger pieces of the drug until they are in the nanoparticle size range.
Aside from providing a more straightforward route to the clinic from a regulatory perspective, they also offer a way to tackle drug adherence issues—i.e. where people don’t take their required medication on time, which causes the effectiveness of the drug to be reduced—by providing a long-lasting, slow release of the drug over a period of 1 to 6 months.
Contributed and Written by Liam Critchley