Structure of Tumor-Suppressing Protein Identified

An international group of researchers led by Carnegie Mellon University physicists Mathias Lösche and Frank Heinrich have established the structure of an important tumor suppressing protein, PTEN. Their findings provide new insights into how the protein regulates cell growth and how mutations in the gene that encodes the protein can lead to cancer. Their findings are published online in Structure, and will appear in the Oct. 6 issue.

Phosphatase and tensin homolog (PTEN) is a known tumor suppressing protein that is encoded by the PTEN gene. When expressed normally, the protein acts as an enzyme at the cell membrane, instigating a complex biochemical reaction that regulates the cell cycle and prevents cells from growing or dividing in an unregulated fashion. Each cell in the body contains two copies of the PTEN gene, one inherited from each parent. When there is a mutation in one or both of the PTEN genes, it interferes with the protein’s enzymatic activity and, as a result inhibits its tumor suppressing ability.

An activated PTEN dimer that contains two non-mutant proteins (A) can transform the functional lipid (D) on the cellular membrane (E) into a chemical form that tunes down cancer predilection. Dimers that contain a mutated protein (B), or PTEN monomers can not transform the functional lipid.

“Membrane-incorporated and membrane-associated proteins like PTEN make up one-third of all proteins in our body. Many important functions in health and disease depend on their proper functioning,” said Lösche, who with other researchers within Carnegie Mellon’s Center for Membrane Biology and Biophysics aim to understand the structure and function of cell membranes and membrane proteins. “Despite PTEN’s importance in human physiology and disease, there is a critical lack of understanding of the complex mechanisms that govern its activity.”Recently, researchers led by Pier Paolo Pandolfi at Harvard Medical School found that PTEN’s tumor suppressing activity becomes elevated when two copies of the protein bind together, forming a dimeric protein.

“PTEN dimerization may be the key to understanding an individual’s susceptibility for PTEN-sensitive tumors,” said Lösche, a professor of physics and biomedical engineering at Carnegie Mellon.In order to reveal how dimerization improves PTEN’s ability to thwart tumor development, researchers needed to establish the protein’s dimeric structure. Normally, protein structure is identified using crystallography, but attempts to crystallize the PTEN dimer had failed. Lösche and colleagues used a different technique called small-angle X–ray scattering (SAXS) which gains information about a protein’s structure by scattering X-rays through a solution containing the protein. They then used computer modeling to establish the dimer’s structure.

They found that in the PTEN dimers, the C-terminal tails of the two proteins may bind the protein bodies in a cross-wise fashion, which makes them more stable. As a result, they can more efficiently interact with the cell membrane, regulate cell growth and suppress tumor formation.Now that more is known about the structure of the PTEN dimer, researchers will be able to use molecular biology tools to investigate the atomic-scale mechanisms of tumor formation facilitated by PTEN mutations. The researchers also hope that their findings will offer up a new avenue for cancer therapeutics.

In addition to Lösche and Heinrich, who are also research associates at the National Institute of Standards and Technology (NIST), and Pandolfi, co-authors of the study include: Srinivas Chakravarthy of Argonne National Laboratory and the Illinois Institute of Technology; Hirsh Nanda of Carnegie Mellon and NIST; Antonella Papa of Monash University in Melbourne; Alonzo H. Ross of the University of Massachusetts Medical School; and Rakesh K. Harishchandra and Arne Gericke of Worcester Polytechnic Institute.

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Capturing cancer: 3-D model of solid tumors explains cancer evolution

This is a three-dimensional model of a tumor showing cell types in varying colors.

Date:August 26, 2015

Source:Harvard University

Summary:Researchers have developed the first model of solid tumors that reflects both their three-dimensional shape and genetic evolution. The new model explains why cancer cells have a surprising number of genetic mutations in common, how driver mutations spread through the whole tumor and how drug resistance evolves.

They’re among the most powerful tools for shedding new light on cancer growth and evolution, but mathematical models of the disease for years have faced an either/or stand off.

Though models have been developed that capture the spatial aspects of tumors, those models typically don’t study genetic changes. Non-spatial models, meanwhile, more accurately portray tumors’ evolution, but not their three-dimensional structure.

A collaboration between Harvard, Edinburgh, and Johns Hopkins Universities including Martin Nowak, Director of the Program for Evolutionary Dynamics and Professor of Mathematics and of Biology at Harvard, has now developed the first model of solid tumors that reflects both their three-dimensional shape and genetic evolution. The new model explains why cancer cells have a surprising number of genetic mutations in common, how driver mutations spread through the whole tumor and how drug resistance evolves. The study is described in an August 26 paper inNature.

“Previously, we and others have mostly used non-spatial models to study cancer evolution,” Nowak said. “But those models do not describe the spatial characteristics of solid tumors. Now, for the first time, we have a computational model that can do that.”

A key insight of the new model, Nowak said, is the ability for cells to migrate locally.

“Cellular mobility makes cancers grow fast, and it makes cancers homogenous in the sense that cancer cells share a common set of mutations. It is responsible for the rapid evolution of drug resistance,” Nowak said. “I further believe that the ability to form metastases, which is what actually kills patients, is a consequence of selection for local migration.”

Nowak and colleagues, including Bartek Waclaw of the University of Edinburgh, who is the first author of the study, Ivana Bozic of Harvard University and Bert Vogelstein of Johns Hopkins University, set out to improve on past models, because they were unable to answer critical questions about the spatial architecture of genetic evolution.

“The majority of the mathematical models in the past counted the number of cells that have particular mutations, but not their spatial arrangement,” Nowak said. Understanding that spatial structure is important, he said, because it plays a key role in how tumors grow and evolve.

In a spatial model cells divide only if they have the space to do so. This results in slow growth unless cells can migrate locally.

“By giving cells the ability to migrate locally,” Nowak said, “individual cells can always find new space where they can divide.

The result isn’t just faster tumor growth, but a model that helps to explain why cancer cells share an unusually high number of genetic mutations, and how drug resistance can rapidly evolve in tumors.

As they divide, all cells — both healthy and cancerous — accumulate mutations, Nowak said, and most are so called “passenger” mutations that have little effect on the cell.

In cancer cells, however, approximately 5 percent are what scientists call “driver” mutations — changes that allow cells to divide faster or live longer. In addition to rapid tumor growth, those mutations carry some previous passenger mutations forward, and as a result cancer cells often have a surprising number of mutations in common.

Similarly, drug resistance emerges when cells mutate to become resistant to a particular treatment. While targeted therapies wipe out nearly all other cells, the few resistant cells begin to quickly replicate, causing a relapse of the cancer.

“This migration ability helps to explain how driver mutations are able to dominate a tumor, and also why targeted therapies fail within a few months as resistance evolves,” Nowak said. “So what we have is a computer model for solid tumors, and it’s this local migration that is of crucial importance.”

“Our approach does not provide a miraculous cure for cancer.” said Bartek Waclaw, “However, it suggests possible ways of improving cancer therapy. One of them could be targeting cellular motility (that is local migration) and not just growth as standard therapies do.”

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The above post is reprinted from materials provided by Harvard University.Note: Materials may be edited for content and length.

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RESEARCHERS MIMIC VIRAL INFECTION IN COLON CANCER STEM CELLS

RESEARCHERS MIMIC VIRAL INFECTION IN COLON CANCER STEM CELLS, IDENTIFY DRUG-GABLE TARGET TO POTENTIALLY ROOT OUT DISEASE, END RELAPSE

(TORONTO, Canada – Aug. 27, 2015) – ​Researchers targeting colorectal cancer stem cells – the root cause of disease, resistance to treatment and relapse – have discovered a mechanism to mimic a virus and potentially trigger an immune response to fight the cancer like an infection.

Watch Dr. Daniel De Carvalho, principal investigator and lead author, discuss his research published today in Cell. Dr. De Carvalho is a scientist at Princess Margaret Cancer Centre. (Photo: UHN)

The discovery, published online today in Cell, illuminates a major shift in understanding anti-tumor mechanisms and identifies a promising druggable target against colorectal cancer stem cells, says principal investigator and lead author Dr. Daniel De Carvalho, a scientist at Princess Margaret Cancer Centre, University Health Network. He is also Assistant Professor in the Department of Medical Biophysics, Faculty of Medicine at University of Toronto.

“By mimicking a virus the potential is to trick the immune system into ‘seeing’ the cancer cells as an infection that needs to be destroyed,” says Dr. De Carvalho. “Our work demonstrates that viral mimicry is a viable anti-tumour strategy.”  Currently, colorectal ‘cancer recurs in about 50 per cent of patients and is among the top three leading causes of cancer-related deaths.

In the laboratory, the research team replicated human colorectal cancer in pre-clinical experiments and used bioinformatics analysis to demonstrate that a low-dose of the chemotherapy drug decitabine targeted the cancer stem cells by inducing viral mimicry.

Decitabine is approved by the U.S. Food and Drug Administration to treat myelodysplastic syndromes and leukemia, and for use in clinical trials for several types of solid-tumour cancers including colorectal. In Dr. De Carvalho’s research, the team discovered that this drug – known as an epigenetic therapy because it chemically modifies DNA – activates a pathway that recognizes viruses.

“We have found a switch to turn on an anti-viral response in colorectal cancer stem cells, which seem to be especially sensitive to it,” says Dr. De Carvalho. This discovery builds on earlier published research from other Princess Margaret scientists, Dr. John Dick, the pioneer of the cancer stem cell field, and Dr. Catherine O’Brien, whose 2007 study established that not all colorectal cancer cells are equal; rather, they are organized in a hierarchy sustained by a subpopulation of stem cells that initiate disease, resist treatment, then self-renew to regrow tumours (Nature).

Dr. De Carvalho says: “Another important implication of our finding is that since decitabine induces an anti-viral response, which is highly immunogenic, it may be useful to combine this agent with immune therapy to further advance personalized cancer medicine by boosting an individual’s natural defenses to fight disease. The next step is to start clinical trials to find out if targeting colon cancer stem cells in this way will result in durable cures.” The research was funded by the Cancer Research Society, Stand Up To Cancer (Epigenetics Dream Team), and The Princess Margaret Cancer Foundation.

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Reprogramming cancer cells back to normal looks feasible, study shows

In many respects, cancer is like a complex software program of life that has got out of control; instead of the code for normal cells, a code for making abnormal cells is executed. Now, a new study in Nature Cell Biology suggests there may be a way to change the code so that cancer cells revert back to normal cells.

Senior investigator Panos Anastasiadis, a professor of cancer biology at the Mayo Clinic in Jacksonville, FL, says their findings represent “an unexpected new biology that provides the code, the software for turning off cancer.”

The discovery centers around the role of adhesion proteins – the glue that keeps cells together to form tissue – and how they interact with microRNAs (miRNAs) – molecules that orchestrate cell programs by regulating gene expression.

The study shows that when normal cells come together, a specific group of miRNAs suppresses genes that encourage cell growth. But, for some reason, this is disrupted in tumor cells, and growth becomes uncontrolled – the hallmark of cancer.

The researchers found when they restored normal miRNA signals in cancer cells, they could reverse the process so growth did not get out of control.

The team became interested in the problem when they tried to reconcile conflicting results that were coming to light about two adhesion proteins: E-cadherin and p120 catenin.

These adhesion proteins are important for normal tissue formation, and for a long time were thought to be tumor suppressors.

The molecules have a ‘good face’ and a ‘bad face’

However, the team began to question the assumptions surrounding E-cadherin and p120 catenin because both molecules are found in tumor cells and appear to be important for tumor growth too.

Prof. Anastasiadis says that led them to wonder if the molecules ” have two faces” – a “good one” that helps keep normal cells behaving correctly and a “bad one” that drives tumor growth.

During their research, the team discovered this seems to be the case, but were no wiser about why. It was not until they studied a new protein – called PLEKHA7 – that associates with E-cadherin and p120 that they found the answer.

They found that the new protein is essential for ensuring E-cadherin and p120 maintain their “good face” and stick to their tumor suppression role.

The researchers say that when PLEKHA7 is lost, the adhesion complex that ensures E-cadherin and p120 keep their “good face” on is disrupted, the miRNAs become misregulated, and E-cadherin and p120 switch to their “bad face” and become tumor-promoting.

Prof. Anastasiadis says they believe this is an “early and somewhat universal event in cancer.” In the vast majority of human tumor samples they looked at, they found the adhesion complex was missing, while E-cadherin and p120 were still present.

He notes this is like a speeding car that has a lot of gas (E-cadherin and p120) but no brakes (the PLEKHA7 complex), and concludes:

“By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to re-establish the brakes and restore normal cell function. Initial experiments in some aggressive types of cancer are indeed very promising.”

The study brings together two fields of biology – cell-to-cell adhesion and miRNA biology – that until now, have not normally worked together. Lead author Dr. Antonis Kourtidis, a researcher in Prof. Anastasiadis’ lab, comments on the result:

“Most significantly, it uncovers a new strategy for cancer therapy.”

In the following video, Prof. Anastasiadis describes the work that went into the study:

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Targeting glucose production in liver may lead to new diabetes therapies

DISABLING A CRITICAL CHECKPOINT FOR CONTROLLING GLUCOSE PRODUCTION IN THE LIVER REDUCES BLOOD SUGAR LEVELS IN MOUSE MODELS OF TYPE 2 DIABETES

Date: September 3, 2015

Source: University of Iowa Health Care

Summary: A biological checkpoint known as the Mitochondrial Pyruvate Carrier is critical for controlling glucose production in the liver and could potentially be a new target for drugs to treat diabetes, new research shows.

High blood sugar is a defining characteristic of Type 2 diabetes and the cause of many of the condition’s complications, including kidney failure, heart disease, and blindness. Most diabetes medications aim to maintain normal blood sugar (glucose) levels and prevent high blood sugar by controlling insulin.

A new University of Iowa study shows that another biological checkpoint, known as the Mitochondrial Pyruvate Carrier (MPC), is critical for controlling glucose production in the liver and could potentially be a new target for drugs to treat diabetes.

The study, led by Eric Taylor, PhD, UI assistant professor of biochemistry, and published Sept. 3 in the journal Cell Metabolism, shows that disabling MPC reduces blood sugar levels in mouse models of Type 2 diabetes.

Glucose is primarily made in the liver and requires the molecular building blocks to pass through specialized cellular compartments called mitochondria. Mitochondria use a small molecule called pyruvate as the starting point for synthesizing glucose, and the pyruvate is imported into the mitochondria through the MPC portal.

Taylor and his colleagues showed that disabling the MPC in mouse livers shuts down this major route of glucose production. However, because glucose is a critical cellular fuel, there are “back-up” mechanisms. When the MPC was disabled in mouse livers, another glucose-producing mechanism was activated to compensate. This alternative mechanism uses molecules from protein as the building blocks for glucose.

“Essentially, what we found is that disruption of the MPC makes the liver less efficient at making glucose and, as a result, the liver burns more fat for energy, makes less cholesterol, and makes less glucose in models of diabetes,” explains Taylor, who also is a member of the Fraternal Order of Eagles Diabetes Research Center at the UI. “This overall change in metabolism matches outcomes that would be therapeutically desirable for people with diabetes.”

The new research is based on earlier work by Taylor’s group and others, which identified the genes for MPC. In the new study, the UI researchers use this genetic information to specifically disrupt MPC activity in animal models. They found that disrupting MPC in normal mice doesn’t cause low blood sugar, or hypoglycemia, which would be important for the safety of any new treatment targeting MPC. In mouse models of Type 2 diabetes, however, loss of the MPC activity in the liver decreases high blood sugar and improves glucose tolerance. The study also suggests that MPC activity contributes to excess glucose production and high blood sugar levels in Type 2 diabetes.

The therapeutic potential of targeting glucose production in the liver is supported by the fact that metformin, the most widely used and staple treatment for Type 2 diabetes, also decreases glucose synthesis in the liver by disrupting mitochondrial metabolism, although the exact mechanisms underlying this drug’s action on mitochondria are controversial.

However, Taylor cautions that additional research will be required to determine if inhibiting MPC activity might be a safe approach for human therapies, especially in people under high levels of physical stress or with other medical complications.

The team plans to extend their studies to cultured human liver cells to determine if disabling the MPC produces the same metabolic effects as seen in the mouse studies, and to make sure that inhibiting this checkpoint does not produce dangerous side effects.

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The above post is reprinted from materials provided by University of Iowa Health Care. Note: Materials may be edited for content and length.

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Disruption of a crucial cellular machine may kill the engine of deadly cancers

Date:September 2, 2015

Source:Baylor College of Medicine

Summary:In a way, cancer resembles a runaway car with a gas pedal stuck to the floor, hurling out of control. Most new targeted cancer therapies seek to fix the gas pedal itself, and thus thwart the aggressive behavior of the tumor. But for many types of cancers, the pedal simply cannot be repaired, so new alternatives are desperately needed. A team of researchers has discovered a way to step on the brakes of some of the deadliest cancers.

In a way, cancer resembles a runaway car with a gas pedal stuck to the floor, hurling out of control. Most new targeted cancer therapies seek to fix the gas pedal itself, and thus thwart the aggressive behavior of the tumor. But for many types of cancers, the pedal simply cannot be repaired, so new alternatives are desperately needed. A team at Baylor College of Medicine has discovered a way to step on the brakes of some of the deadliest cancers.

“Almost thirty percent of all malignancies are driven by the cancer gene MYC. No one has been able to turn this gene off, and thus patients with MYC-driven cancers often lack effective therapies,” said Dr. Thomas (Trey) F. Westbrook, associate professor in the department of biochemistry and molecular biology and molecular and human genetics at Baylor. “Like killing the engine of a runaway car, we have found a new way to kill cancers driven by MYC. We can do this by inhibiting a molecular machine within the cancer cell called the spliceosome.” A report on their work appears online in the journal Nature.

Westbrook and colleagues have discovered that MYC-driven cancers depend on the spliceosome to survive.

“The spliceosome is a complex machine composed of many proteins,” said Tiffany Hsu, an M.D./Ph.D student in the Medical Scientist Training Program and lead author of the study. “This machine helps cancers ‘read’ their instruction manual by deleting unnecessary steps. When we inhibit the spliceosome, cancers can no longer understand their instructions for growth and survival.”

In their study, Westbrook, Hsu and colleagues found that inhibition of the spliceosome using a new drug kills tumor cells but leaves noncancerous tissues unaffected in mouse models.

“This study is a promising step towards helping patients with deadly cancers driven by MYC. We’re also excited to discover a new side to the MYC oncogene, which is one of the most intensely studied but enigmatic cancer genes,” said Hsu.

MYC rewires the cancer cell, and changes many things like production of the building blocks that every tumor cell needs. But this rewiring also confers new stresses and new vulnerabilities in cancer cells. “If we could learn how to exacerbate those stresses, we could kill the cancer cell without harming normal tissues,” said Westbrook, also a member of the Dan L. Duncan Cancer Center, an NCI-Designated Comprehensive Cancer Center, at Baylor. “The spliceosome may be a critical piece of the puzzle.”

While spliceosome inhibitors are unlikely to provide an answer to all cancers, they are promising candidates for some aggressive malignancies like triple negative breast cancer, a common and particularly virulent form of the disease.

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The above post is reprinted from materials provided by Baylor College of Medicine. Note: Materials may be edited for content and length.

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