Tag: cancer

Antibody rigidity regulates immune activity

Antibody rigidity regulates immune activity

Scientists at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to stimulate immune activity to fight off cancer, using the ESRF’s structural biology beamlines, among others.

The interdisciplinary study, published in Science Immunology, revealed how changing the flexibility of the antibody could stimulate a stronger immune response. The findings have enabled the team to design antibodies to activate important receptors on immune cells to “fire them up” and deliver more powerful anti-cancer effects. The researchers believe their findings could pave the way to improve antibody drugs that target cancer, as well as automimmune diseases.

In the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of understanding of how to stimulate the receptors to the right level. The problem being that if antibodies are too active they can become toxic. Previous research by the same team had shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, since it is more active than other antibody types. However, the reason why it is more active had not been determined. What was known, however, is that the structure between the antibody arms, the so called hinges, changes over time.

This latest research harnesses this property of the hinge and explains how it works: the researchers call this process “disulfide-switching”. In their study, the team analysed the effect of modifying the hinge and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Read more on the ESRF website

Image: Flexibility of the monoclonal antibody F(ab) arms is conferred by the hinge region disulphide structure

Credit: C. Orr

Paving the way for more effective pancreatic cancer research

Paving the way for more effective pancreatic cancer research

A team of scientists led by the University of Surrey used Diamond’s B16 Beamline, a flexible and versatile beamline for testing new developments in optics and detector technology and for trialling new experimental techniques, to better understand the structure of cancer cells. 

By using the synchrotron, the team were able to complete sophisticated examinations of the characteristics of cell structures at a nano level and even at an atomic scale and to investigate how cells and materials interact with each other.  

To improve cancer screening and treatment, researchers need accurate models of cancer tissues on which to experiment. Previous research made significant progress in building accurate, novel 3D models which mimic features of a pancreatic tumour, such as structure, porosity and protein composition.

Read more on the Diamond website

Image: Inside the experimental hutch at Diamond’s B16 beamline.

Credit: Diamond Light Source

Cell cytoskeleton as target for new active agents

Cell cytoskeleton as target for new active agents

Through a unique combination of computer simulations and laboratory experiments, researchers at the Paul Scherrer Institute PSI have discovered new binding sites for active agents – against cancer, for example – on a vital protein of the cell cytoskeleton. Eleven of the sites hadn’t been known before. The study is published in the journal Angewandte Chemie International Edition.

The protein tubulin is an essential building block of the so-called cell cytoskeleton. In cells, tubulin molecules arrange themselves into tube-like structures, the microtubule filaments. These give cells their shape, aid in transporting proteins and larger cellular components, and play a crucial role in cell division.

Thus tubulin performs diverse functions in the cell and in doing so interacts with numerous other substances. “Tubulin can bind an astonishing number of different proteins and small molecules, several hundred for sure,” says Tobias Mühlethaler, a doctoral candidate in the PSI Laboratory of Biomolecular Research and first author of the study. The functions of the protein are guided by means of such bonds. Also, many drugs dock on tubulin and take effect, for example, by preventing cell division in tumours.

Read more on the PSI website

Image: The research team in front of the Swiss Light Source (from left): Andrea Prota, Tobias Mühlethaler and Michel Steinmetz


Credit: Paul Scherrer Institute/Mahir Dzambegovic

How cellular proteins control cancer spread

How cellular proteins control cancer spread

New finding may help focus the search for anti-cancer drugs

A new insight into cell signals that control cancer growth and migration could help in the search for effective anti-cancer drugs. A team of researchers has revealed key biochemical processes that advance our understanding of colorectal cancer, the third most common cancer among Canadians.

Using the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan, scientists from McGill University and Osaka University in Japan were able to unlock the behavior of an enzyme involved in the spread of cancer cells. The team found that there is a delicate interaction between the enzyme, PRL3, and another protein that moves magnesium in and out of cells. This interaction is crucial to colorectal cancer growth.

A new insight into cell signals that control cancer growth and migration could help in the search for effective anti-cancer drugs. A team of researchers has revealed key biochemical processes that advance our understanding of colorectal cancer, the third most common cancer among Canadians.

Using the CMCF beamline at the Canadian Light Source (CLS) at the University of Saskatchewan, scientists from McGill University and Osaka University in Japan were able to unlock the behavior of an enzyme involved in the spread of cancer cells. The team found that there is a delicate interaction between the enzyme, PRL3, and another protein that moves magnesium in and out of cells. This interaction is crucial to colorectal cancer growth.

Read more on the Canadian Light Source website

Image: Members of the Gehring research laboratory discussing the results of a protein purification.

Promising new drug carrier could improve bone repair and cancer treatments

Promising new drug carrier could improve bone repair and cancer treatments

Researchers from Western University and the Shanghai Institute of Ceramics, Chinese Academy of Sciences used the Canadian Light Source (CLS) at the University of Saskatchewan to explore a promising drug carrier that could be used to deliver cancer treatments and therapeutics for severe injuries.

Their work advances drug carrier technology to make the carrier more compatible with our bodies. This allows the drug carrier to deliver the desired treatment precisely to a tumor, or to allow a slower release of the medicine. In a new paper published in The Royal Society of Chemistry, the team investigated using calcium phosphate as a potential drug carrier. Their approach uses phosphate from the biomolecule that stores and transports energy in our cells, which allows the carrier to be more compatible with the human body. Using this drug delivery system solves the limitations of other carriers, including biocompatibility and toxicity. Their carrier is highly compatible with our biological system, allowing for a better response while also being non-toxic.

“Calcium phosphate is an important biomaterial in bones and teeth. If you can use this material as a drug carrier then you don’t need to worry about what happens after it is done with delivery,” said Tsun-Kong (TK) Sham, Professor of Chemistry at Western University.

Read more on the Canadian Light Source website

Image: TK Sham, a Professor of Chemistry at Western University, using beamlines at the CLS.

Faster diagnosis of esophageal cancer

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

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

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

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

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

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

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

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

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

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.