Faster diagnosis of esophageal cancer

Scientists from SOLARIS National Synchrotron Radiation Centre (Kraków, Poland), University of Exeter (UK), Beckman Institute (University of Illinois at Urbana-Champaign – USA), and Institute of Nuclear Physics Polish Academy of Sciences (Kraków, Poland) performed research that will facilitate the rapid and automated diagnosis of esophageal cancer.

Dr. Tomasz Wróbel`s group focuses on cancer detection through a combination of Infrared Imaging (IR) and the use of Machine Learning (ML) algorithms. Thanks to this approach, it is possible to develop an effective model, which will allow histopathologists to confirm the diseased area automatically and in a much shorter time.

Infrared Imaging (IR), which will soon also be available on the newly built beamline at SOLARIS, has found widespread use in biomedical research over the last couple of decades and is currently being introduced into clinical diagnostics.

Read more on the Solaris website

Image: The above graphic shows two esophageal biopsies: the top of the graphic contains a biopsy taken from a patient suffering from esophageal cancer, the bottom of the graphic contains a biopsy taken from a healthy patient. In the left part of the graphic, microscopic images of the mentioned biopsies are visible after the H&E staining (Hematoxylin and Eosin) (in this image of the stained biopsy, the histopathologist visually assigns tissue types), in the middle of the graphic, biopsy images obtained using infrared imaging are visible, the right part of the graphic presents a histological picture of a biopsy obtained after assigning tissues and structures to three classes (cancer, other, benign) by Machine Learning (ML).

Red – cancer
Blue – other
Green – benign

Developing microbeam radiation therapy for inoperable cancer

An innovative radiation treatment that could one day be a valuable addition to conventional radiation therapy for inoperable brain and spinal tumors is a step closer, thanks to new research led by University of Saskatchewan (USask) researchers at the Canadian Light Source (CLS).

Microbeam radiation therapy (MRT) uses very high dose, synchrotron-generated X-ray beams—narrower than a human hair—to blast tumours with radiation while sparing healthy tissue. The idea is that MRT would deliver an additional dose of radiation to a tumor after maximum conventional radiation therapy has been tried, thereby providing patients with another treatment that could extend their lives. 

But the longstanding questions have been: What is the optimal X-ray energy range of the MRT radiation dose that will both penetrate the thickness of the human body and still spare the healthy cells? How can the extremely high radiation doses be delivered and measured with the accuracy necessary for human treatment?

Read more on the Canadian Light Source website

Image : Farley Chicilo at the Canadian Light Source.

Imaging how anticancer compounds move inside the cells

Chemotherapeutics are key players in the clinical setting to fight most types of cancer, and novel chemicals hold the promise to facilitate new and unique intracellular interactions that modulate the cell machinery and destroy the tumour cells. Equally necessary are new tools that enable the unequivocal location and quantification of such molecules in the intracellular nano-space, so that their therapeutic action is fully understood.

Researchers from IMDEA Nanociencia, the ALBA Synchrotron, the European Synchrotron Radiation Facility (ESRF) and the National Centre for Biotechnology (CNB) have developed a new family of organo-iridium drug candidates about a hundred times more potent than the clinically used drug cisplatin.
In order to understand the therapeutic potential of the compound, it is mandatory to accurately localize its fate within the cell ultrastructure with minimal perturbation. To this aim researchers have correlated on the same cell, for the first time, two 3D X-ray imaging techniques with a resolution of tenths of nanometers: cryo soft X-ray tomography, at MISTRAL beamline at ALBA Synchrotron, and cryo X-ray fluorescence tomography, at ID16A beamline at ESRF. These techniques help elucidate the 3D architecture of the whole cell and to reveal the intracellular location of different atomic elements, respectively.

>Read more on the ALBA website

ALS reveals vulnerability in cancer-causing protein

A promising anticancer drug, AMG 510, was developed by Amgen with the help of novel structural insights gained from protein structures solved at the Advanced Light Source (ALS).

Mutations in a signaling protein, KRAS, are known to drive many human cancers. One specific KRAS mutation, KRAS(G12C), accounts for approximately 13% of non-small cell lung cancers, 3% to 5% of colorectal cancers, and 1% to 2% of numerous other solid tumors. Approximately 30,000 patients are diagnosed each year in the United States with KRAS(G12C)-driven cancers.

Despite their cancer-triggering significance, KRAS proteins have for decades resisted attempts to target their activity, leading many to regard these proteins as “undruggable.” Recently, however, a team led by researchers from Amgen identified a small molecule capable of inhibiting the activity of KRAS(G12C) and driving anti-tumor immunity. Protein crystallography studies at the ALS provided crucial information about the structural interactions between the potential drug molecule and KRAS(G12C).

>Read more on the Advanced Light Source website

Image: A structural map of KRAS(G12C), showing the AMG 510 molecule in the binding pocket. The yellow region depicts where AMG 510 covalently attaches to the KRAS protein.
Credit: Amgen

Learning how breast cancer cells evade the immune system

Cancer cells have ways to evade the human immune system, but research at UK’s Synchrotron, Diamond could leave them with nowhere to hide.

Announced on World Cancer Day, the latest research (published in Frontiers in Immunology) by Dr Vadim Sumbayev, together with an international team of researchers, working in collaboration with Dr Rohanah Hussain and Prof Giuliano Siligardi at Diamond Light Source.  They have been investigating the complex defence mechanisms of the human immune system and how cancer cells in breast tumours avoid it. In particular, they sought to understand one of the biochemical pathways leading to production of a protein called galectin-9, which cancer cells use to avoid immune surveillance. Dr Vadim Sumbayev explains, The human immune system has cells that can attack invading pathogens, protecting us from bacteria and viruses. These cells are also capable of killing cancer cells, but they don’t. Cancer cells have evolved defence mechanisms that protect them from our immune system, allowing them to survive and replicate, growing into tumours that may then spread across the body. Unfortunately, the molecular mechanisms that allow cancer cells to escape host immune surveillance remain poorly understood.  So, with a growing body of evidence suggesting that some solid tumours also use proteins called Tim-3 and galectin-9 and to evade host immune attack, we chose to study the activity of this pathway in breast and other solid and liquid tumours. 

>Read more on the Diamond Light Source website

Image: Breast cancer cell-based pathobiochemical pathways showing LPHN-induced activation of PKCα, which triggers the translocation of Tim-3 and galectin-9 onto the cell surface which is required for immune escape.

New biocompatible nanoparticles for breast cancer therapy

A research team has studied the efficacy of new CHO/PA polymeric nanoparticles for the sustained delivery of a drug used in breast cancer therapy. Some of the experiments have been carried out in the NCD-SWEET beamline at ALBA.

According to data from the Spanish Association against Cancer (AECC) observatory, breast cancer is the second most common type of cancer in Spain with 33,307 new cases in 2019. The number of deceased has reached 6,689 this year. Many research groups are exploring new ways to fight against this disease.
Dasatinib, an FDA-approved compound for the treatment of chronic myeloid leukemia, has become a potential candidate for the treatment of other cancers. It has been recently demonstrated that it could have a relevant role in breast cancer therapy. However, the solubility of this compound is extremely low, leading to poor absorption by the organism. Thus, the administration of a higher dosage is needed in order to obtain a better effect.
An alternative solution to enhance its therapeutic effect is the development of polymeric nanoparticles for a sustained and controlled delivery of the drug.
>Read more on the ALBA website

Image: 2D SAXS and WAXS patterns of the CHO/PA nanoparticles recorded at NCD-SWEET beamline, which confirm the lack of well-structured mesophase.

 

A research, led by the ALBA Synchrotron and funded by the European project NANOCANCER, has analysed the impact of nanoparticles in radiotherapy of glioma tumour cells.

Combining radiotherapy with nanoparticles can increase the efficacy of cancer treatments. The experiment has been carried out at the MIRAS beamline of ALBA, devoted to infrared microspectroscopy.

The use of nanotechnology in medicine is nothing short of revolutionary. Nanosensors for diagnosis, nanoparticles for drug delivery or nanodevices that can regenerate damaged tissue are changing the way we face and treat several diseases.

Combining radiotherapy with nanoparticles is a promising strategy to increase the efficacy of cancer treatments. High-atomic number nanoparticles are used as tumour radiosensitizers: tumour cells previously loaded with nanoparticles enhance the radiation effects when exposed to radiotherapy. “It’s a kind of knock-on effect; the interaction of the radiation with the nanoparticles generates short-range secondary radiation that induces a local dose enhancement in the tumour cells. However, the mechanisms underlying the synergistic effects involved in these techniques are not clearly understood’, says Immaculada Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.

>Read more on the ALBA website

Image: Researcher Imma Martínez-Rovira, Marie Curie scientist of ALBA and expert in the development of innovative radiotherapy approaches.

Structure and functional binding epitopes of VISTA

V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint protein involved in the regulation of T cell activity. Checkpoint proteins are overexpressed by cancer cells or surrounding immune cells and prevent anti-tumor activity by co-opting natural regulation mechanisms to escape immune clearance. Compared to healthy tissues, VISTA is upregulated on tumor infiltrating leukocytes, including high expression on myeloid-derived suppressor cells (MDSCs). Through VISTA signaling, these inhibitory immune cells prevent effective antigen presentation and indirectly promote tumor growth. VISTA is implicated in a number of human cancers including skin (melanoma), prostate, colon, pancreatic, ovarian, endome­trial, and non-small cell lung. VISTA is a known member of the B7 protein family but the mechanism of action is still unclear as VISTA has been shown to function as both a ligand1,2 and a receptor3.  In the model of VISTA as a receptor, the proposed ligand of interaction is V-set and immunoglobulin domain containing 3 (VSIG3)4,5.

>Read more on the SSRL website

Image: Structure of human VISTA with extended C-C’ loop (blue), mapped VSTB/VSIG3 binding epitope (red), and disulfide bonds (yellow).

Preventing tumour metastasis

Researchers at the Paul Scherrer Institute, together with colleagues from the pharmaceutical company F. Hoffmann-La Roche AG, have taken an important step towards the development of an agent against the metastasis of certain cancers.

Using the Swiss Light Source, they deciphered the structure of a receptor that plays a crucial role in the migration of cancer cells. This makes it possible to identify agents that could prevent the spread of certain cancer cells via the body’s lymphatic system. The researchers have now published their results in the journal Cell.
When cancer cells spread in the body, secondary tumours, called metastases, can develop. These are responsible for around 90 percent of deaths in cancer patients. An important pathway for spreading the cancer cells is through the lymphatic system, which, like the system of blood vessels, runs through the entire body and connects lymph nodes to each other. In the migration of white blood cells through this system, for example to coordinate the defense against pathogens, one special membrane protein, the chemokine receptor 7 (CCR7) plays an important role. It sits in the shell of the cells, the cell membrane, in such a way that it can receive external signals and relay them to the interior. Within the framework of a joint project with the pharmaceutical company F. Hoffmann-La Roche AG (Roche), researchers at the Paul Scherrer Institute (PSI) have for the first time been able to decipher the structure of CCR7 and lay the foundation for the development of a drug that could prevent metastasis in certain prevalent cancer types, such as colorectal cancer.

Read more on the SLS at PSI website

Image: Steffen Brünle (right) and Jörg Standfuss at the apparatus they use to separate proteins from each other. For their study, the researchers modified insect cells to produce a human protein. To extract this from the cell, the cell was destroyed, and then the protein, whose structure the researchers have now elucidated, was separated with the help of this apparatus.
Credit: Paul Scherrer Institute/Markus Fischer

Revolutionary discovery in leukemia research

Leukemia affects over 6,000 Canadians per year. A team of researchers used the Canadian Light Source (CLS) at the University of Saskatchewan to discover a new way to kill leukemia cancer cells. When the scientists hyperactivated the “garbage disposal systems” of leukemia cells, it caused the cancer to die.
The researchers believe this finding will transform the direction of cancer therapy by focusing on a protein that was previously believed to be impossible to target. Their study was featured on the cover of the journal Cancer Cell.
“It was a major advancement to visualize the structural biology through crystallography facilities at CLS and to prove conclusively that ONC201 binds and hyperactivates ClipP proteases to induce cell death,” said co-author Dr. Aaron Schimmer from the Princess Margaret Cancer Centre and the University of Toronto.

>Read more on the Canadian Light Source website

Image: Interface of two heptamer rings in an apparently closed conformation of human mitochondrial ClpP.

The interaction between two proteins involved in skin mechanical strength

A research team from the Centro de Investigación del Cáncer of the Universidad de Salamanca has obtained a detailed 3D image of the union between two hemidesmosomal proteins.

The structure of this complex has been unveiled using XALOC beamline techniques, at the ALBA Synchrotron. The results, published in “Structure”, provide insights to understand how these epithelial adhesion structures are formed. Researchers from Centro de Investigación del Cáncer – Instituto de Biología Molecular y Celular del Cáncer of Salamanca, from Centro Universitario de la Defensa in Zaragoza, and from the Netherlands Cancer Institute in Amsterdam have described how two essential proteins interact to each other in order to join epidermis and dermis together. This study reveals at atomic scale how the binding between two hemidesmosomal proteins called integrin α6β4 and BP230 takes place.
Epithelial tissues, such as epidermis, settle on fibrous sheets called basement membrane, formed by extracellular matrix proteins. The junction between epithelia and basement membrane happens through hemidesmosomes, multi-protein complexes located at the membrane of epithelial cells. Integrin α6β4 is an essential protein of the hemidesmosomes, which adheres to proteins of the basement membrane. Inside the cell cytoplasm, plectin and BP230 proteins bind to α6β4 and connect it to the intermediate filaments of the cytoskeleton. Genetic or autoimmune alterations that affect the hemidesmosomal proteins reduce skin resistance and cause diseases such as bullous pemphigoid and various types of epidermolysis bullosa.

>Read more on the ALBA website

Image: Structure of β4(WT)-BP230 complex.

Researchers create the first maps of two melatonin receptors essential for sleep

A better understanding of how these receptors work could enable scientists to design better therapeutics for sleep disorders, cancer and Type 2 diabetes.

An international team of researchers used an X-ray laser at the Department of Energy’s SLAC National Accelerator Laboratory to create the first detailed maps of two melatonin receptors that tell our bodies when to go to sleep or wake up, and guide other biological processes. A better understanding of how they work could enable researchers to design better drugs to combat sleep disorders, cancer and Type 2 diabetes. Their findings were published in two papers today in Nature.

The team, led by the University of Southern California, used X-rays from SLAC’s Linac Coherent Light Source (LCLS) to map the receptors, MT1 and MT2, bound to four different compounds that activate them: an insomnia drug, a drug that mixes melatonin with the antidepressant serotonin, and two melatonin analogs.

>Read more on the LCLS at SLAC website

Image: The researchers showed that both melatonin receptors contain narrow channels embedded in the cell’s fatty membranes. These channels only allow melatonin, which can exist happily in both water and fat, to pass through, preventing serotonin, which has a similar structure but is only happy in watery environments, from binding to the receptor. They also uncovered how some much larger compounds only target MT1 despite the structural similarities between the two receptors.
Credit: Greg Stewart/SLAC National Accelerator Laboratory


Understanding the viruses that kill cancer cells

Taking inspiration from virology to find better treatments for cancer

There are some viruses, called oncolytic viruses, that can be trained to target and kill cancer cells. Scientists in the field of oncolytics want to engineer these viruses to make them safer and more effective so they can be used to treat more people and different types of cancers. To achieve this, they first have to fully understand at the molecular level all the different ways that the virus has evolved to infect healthy cells and cause disease. A research team from Cardiff University set out to better understand how a protein on the surface of a virus often used to kill cancer, called an adenovirus, binds to human cells to cause an infection. Using X-ray crystallography, the team was able to determine the structure of one the key adenovirus proteins. Using this information and after extensive computational analysis, the research team realised the virus was not binding the receptor on the cells that was originally thought. This has important implications for the development of new virotherapies and engineering of viruses to treat cancer. The more thoroughly the researchers can understand how the adenoviruses interact with cancer cells at the molecular level, the more safe and effective treatments can be brought to clinical trial in the future.

>Read more on the Diamond Light Source website

Absorber captures excess chemotherapy drugs

The work opens up a new route to fighting cancer that minimizes drug toxicity and enables personalized, targeted, high-dose chemotherapy.

Most anticancer drugs are poisonous, so doctors walk a delicate line when administering chemotherapy. A dose must be sufficient to kill or stop the growth of cancer cells in the target organ, but not high enough to irreparably damage a patient’s other organs. To avoid this, doctors can thread catheters through the bloodstream to deliver chemotherapy drugs directly to the site of the tumor—a method known as intra-arterial chemotherapy. Still, typically more than half of the dose injected into the body escapes the target organ. Several years ago, researchers began working on a major improvement: placing a device “downstream” of the targeted organ to filter out excess chemo so that much less of the drug reaches the body as a whole.

>Read more on the Advanced Light Source

Image: (extract, see here the full image)
(a) Diagram of the proposed approach for drug capture using a 3D-printed cylindrical absorber. (b) Chemical structure of doxorubicin, the chemotherapy drug used in this study. (c) Schematic of the endovascular treatment of liver cancer. Excess drug molecules are captured by the absorber in the vein draining the organ. An introducer sheath guides the absorber to the desired location via a guide wire.

A new molecule could help put the STING on cancer

The protein STING (stimulator of interferon genes) is a component of the innate immune system. It plays a major role in the immune response to cancer, and abnormal STING signaling has been shown to be associated with certain cancers. Immunomodulatory approaches using agonists to target STING signaling are therefore being investigated as anticancer treatments. However, the compounds in clinical trials typically are injected intratumorally in patients with solid cancers. In this study, researchers discovered a novel STING agonist, known as an amidobenzimidazole (ABZI), which can be given by intravenous injection and could therefore potentially open up its evaluation as a treatment for hard-to-reach cancers. Using x-ray diffraction data collected at the U.S. Department of Energy’s Advanced Photon Source (APS), researchers from GlaxoSmithKline (GSK) investigated ABZI compounds and STING. Their results, published in the journal Nature, may have important implications for anticancer immunotherapy.

STING is a protein that mediates innate immunity, and one function of the STING signaling pathway is in mobilizing an immune response against tumors. STING proteins can be activated by cyclic dinucleotides, small molecules that are made by the cytosolic DNA sensor, cGAS, upon sensing of DNA leaking out of the nucleus as a result of DNA damage, including that which might be associated with cancer development.

>Read more on the Advanced Photon Source at Argonne National Lab.

Figure: X-ray crystal structure of the STING protein bound to one of the new molecules.

Clear view of “Robo” neuronal receptor opens door for new cancer drugs

During brain development, billions of neuron nerve cells must find accurate pathways in the brain in order to form trillions of neuronal circuits enabling us to enjoy cognitive, sensory and emotional wellbeing.

To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons stay on the right path. In a new study published in Cell, researchers from Bar-Ilan University and Tel Aviv University in Israel, EMBL Grenoble in France and University of Exeter in the UK report on their discovery of the intricate molecular mechanism that allows a key guidance receptor, “Robo”, to react to signals in its environment.

One of the most important protein signaling systems that guide neurons consists of the cell surface receptor “Robo” and its external guidance cue, “Slit”. “Slit and Robo can be identified in virtually all animals with a nervous system, from a 1 mm-long nematode all the way to humans,” explains researcher Yarden Opatowsky, associate professor and head of the Laboratory of Structural Biology at Bar-Ilan University and who led the research.

>Read more on the European Synchrotron website

Image: A surface representation of the crystal structure of the extracellular portion of human Robo2. The yellow region represents the domain where dimerisation takes place. Here, we see it blocked by the other domains, meaning dimerisation cannot take place and that Robo2 is inactivated.
Credit: Y. Opatowsky.