MIT News - Topic - Cancer
Sat, 04 Feb 2012 12:34:46 +0100

Metabolic errors can spell doom for DNA
Many critical cell functions depend on a class of molecules called purines, which form half of the building blocks of DNA and RNA, and are a major component of the chemicals that store a cell’s energy. Cells keep tight control over their purine supply, and any disruption of that pool can have serious consequences.

In a new study, MIT biological engineers have precisely measured the effects of errors in systems for purine production and breakdown. They found that defects in enzymes that control these processes can severely alter a cell’s DNA sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer.

DNA usually consists of a sequence of four building blocks, or nucleotides: adenine, guanine, cytosine and thymine (the A, G, C and T “letters” that make up the genetic code). Guanine and adenine are purines, and each has a close structural relative that can take its place in DNA or RNA. When these nucleotides, known as xanthine and hypoxanthine, are mistakenly inserted into DNA, they cause mutations. They can also interfere with the function of messenger RNA (mRNA), which carries DNA’s instructions to the rest of the cell, and the RNA molecules that translate mRNA into proteins.

“A cell needs to control the concentrations very carefully so that it has just the right amount of building blocks when it’s synthesizing DNA. If the cell has an imbalance in the concentrations of those nucleotides, it’s going to make a mistake,” says Peter Dedon, a professor of biological engineering at MIT and senior author of the study, which is appearing in the Proceedings of the National Academy of Sciences the week of Jan. 30.

In addition to forming the backbone of DNA and RNA, purines are also a major component of ATP, the cell’s energy currency; other molecules that manage a cell’s energy flow; and small chemical cofactors required for the activity of thousands of cell enzymes.

Abnormal metabolism

Dozens of enzymes are involved in purine metabolism, and it has long been known that malfunction of those enzymes can have adverse effects. For example, losing a purine salvage enzyme, which recovers purine nucleotides from degraded DNA and RNA, leads to high blood levels of uric acid, causing gout and kidney stones — and in extreme cases, a neurological disorder called Lesch-Nyhan syndrome. Losing another salvage enzyme produces a disease called severe combined immunodeficiency.

Abnormal purine metabolism can also lead to side effects for people taking a class of drugs called thiopurines. In some people, these drugs, often used to treat leukemia, lymphoma, Crohn’s disease, rheumatoid arthritis and organ-transplant rejection, can be metabolized into toxic compounds. Genetic testing can reveal which patients should avoid thiopurine drugs.

In the new study, Dedon and his colleagues disrupted about half a dozen purine metabolism enzymes in E. coli and yeast. After altering the enzymes, the researchers measured how much xanthine and hypoxanthine was integrated into the cells’ DNA and RNA, using a highly sensitive mass spectrometry technique they had previously developed to study DNA and RNA damage caused by inflammation.

They found that the malfunctioning enzymes could produce dramatic increases — up to 1,000-fold — in the amounts of hypoxanthine incorporated into DNA and RNA in place of adenine. However, they saw very little change in the amount of xanthine inserted in place of guanine. 

Chris Mathews, a professor emeritus of biochemistry and biophysics at Oregon State University, says the finding could help researchers better understand how defects in purine metabolism produce disease. “This paper opens the door to numerous studies — for example, looking into the biological effects resulting from the accumulation of abnormal bases in DNA and RNA,” says Mathews, who was not involved in this study.

Scientists have found quite a bit of genetic variation in purine metabolic enzymes in humans, so the research team plans to investigate the impact of those human variants on xanthine and hypoxanthine insertion into DNA. They are also interested in studying the metabolism of the other two nucleotides found in DNA, cytosine and thymine, which are pyrimidines.
Tue, 31 Jan 2012 05:00:00 +0000

Seeing what’s inside a tumor
Gliomas, the most common types of brain tumor, are also among the deadliest cancers: Their mortality rate is nearly 100 percent, in part because there are very few treatments available. 

A team of researchers from MIT, Harvard University, Massachusetts General Hospital (MGH) and Agios Pharmaceuticals has now developed a way to identify a particular subset of brain tumors, which may help doctors choose treatments and create new drugs that target the disease’s underlying genetic mutation.

Scientists have known for several years that many brain tumors involve a mutation in the gene for an enzyme called isocitrate dehydrogenase (IDH). This enzyme is involved in cell metabolism — the process of breaking down sugar molecules to extract energy from them. IDH mutations are found in up to 86 percent of low-grade gliomas, which have a better prognosis than high-grade gliomas, also called glioblastomas. Patients with low-grade gliomas can survive for years, though the tumors almost always prove fatal.

Several pharmaceutical companies are now pursuing drugs that target IDH, in hopes of halting tumor growth. Some of those drugs may enter clinical trials within the year, says Matthew Vander Heiden, a member of the David H. Koch Institute for Integrative Cancer Research at MIT.

Vander Heiden is part of the team that developed imaging technology to reveal whether brain tumors have the IDH mutation, which could help researchers monitor whether potential drugs are having the desired effect. The researchers described their technique in the Jan. 11 online edition of Science Translational Medicine.

Unambiguous detection

When IDH is mutated, a tumor cell begins to produce vast quantities of a molecule called 2-hydroxyglutarate (2-HG). Previous research has shown that 2-HG interferes with the regulation of DNA expression, causing the cell to revert to an immature state conducive to uncontrolled growth. (IDH mutations are also found in some forms of leukemia and, rarely, in other cancers.)

The new imaging technique uses magnetic resonance (MR) spectroscopy, which analyzes the magnetic properties of atomic nuclei, to locate 2-HG in the brain. Other researchers have tried to image 2-HG with MR spectroscopy, but found it difficult to distinguish 2-HG from some of the brain’s common metabolites, such as glutamate and glutamine.

MGH researchers led by Greg Sorensen and Ovidiu Andronesi, the lead author of the Science Translational Medicine paper, found a way to unambiguously detect 2-HG by doing the MR scans in two dimensions, which gives enough information to conclusively distinguish 2-HG from similar compounds. The imaging technique does not require any specialized equipment; it can be done with the clinical MRI scanners already found in most hospitals.

“The most exciting thing about this is it opens up the possibility that as drugs against gliomas come online, you could know which patients with brain tumors to put in the clinical trials, and you would know if the drug you’re giving them is actually doing what it’s supposed to do,” says Vander Heiden, the Howard S. and Linda B. Stern Career Development Professor of Biology at MIT.

Currently, the only way to measure 2-HG levels is by taking a brain biopsy and doing mass spectrometry on the tissue. This is commonly done when a brain tumor is first diagnosed, but can’t be done on a regular basis, says Hai Yan, an assistant professor of pathology at Duke University.

“If you can detect [2-HG] in the tissue or blood, it would allow physicians to tell if treatments for the tumor have been effective or not,” says Yan, who was not involved in this research.


Thu, 12 Jan 2012 05:00:01 +0000

How cancer cells get by on a starvation diet
Cancer cells usually live in an environment with limited supplies of the nutrients they need to proliferate — most notably, oxygen and glucose. However, they are still able to divide uncontrollably, producing new cancer cells.

A new study from researchers at MIT and the Massachusetts General Hospital (MGH) Cancer Center helps to explain how this is possible. The researchers found that when deprived of oxygen, cancer cells (and many other mammalian cells) can engage an alternate metabolic pathway that allows them to use glutamine, a plentiful amino acid, as the starting material for synthesizing fatty molecules known as lipids. These lipids are essential components of many cell structures, including cell membranes.

The finding, reported in the Nov. 20 online edition of Nature, challenges the long-held belief that cells synthesize most of their lipids from glucose, and raises the possibility of developing drugs that starve tumor cells by cutting off this alternate pathway.

Lead author of the paper is Christian Metallo, a former postdoc in the lab of Gregory Stephanopoulos, the William Henry Dow Professor of Chemical Engineering and Biotechnology at MIT and a corresponding author of the paper. Othon Iliopoulos, an assistant professor of medicine at Harvard Medical School and MGH, is the paper’s other corresponding author. 

Alternate pathways

Much of the body’s supply of oxygen and glucose is carried in the bloodstream, but blood vessels often do not penetrate far into the body of tumors, so most cancer cells are deficient in those nutrients. This means they can’t produce fatty acids using the normal lipid-synthesis pathway that depends mostly on glucose.

In prior work, Stephanopoulos’ lab identified a metabolic pathway that uses glutamine instead of glucose to produce lipids; the new paper shows that this alternate pathway is much more commonly used than originally thought. The researchers found that in both normal and cancerous cells, lack of oxygen — a state known as hypoxia — provokes a switch to the alternate pathway.

In a normal oxygen environment, 80 percent of a cell’s new lipids come from glucose, and 20 percent from glutamine. That ratio is reversed in a hypoxic environment, Stephanopoulos says.

“We saw, for the first time, cancer cells using substrates other than glucose to produce lipids, which they need very much for their rapid growth,” Iliopoulos explains. “This is the first step to answering the question of how new cell mass is synthesized during hypoxia, which is a hallmark of human malignancies.”

The glutamine may come from within the cell or from neighboring cells, or the extracellular fluid that surrounds cells.

“There’s protein everywhere,” says Matthew Vander Heiden, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology at MIT and a co-author of the Nature paper. “The new pathway allows cells to conserve what glucose they do have, perhaps to make RNA and DNA, and then co-opt the new pathway to make lipids so they can grow under low oxygen.”

The switch from glucose to glutamine is triggered by low oxygen and allows cancer cells to thrive and proliferate in an environment with minimal glucose, though it is not clear how this is done. “Elucidating the molecular mechanism regulating this switch would be important in understanding regulation of cancer metabolism,” Stephanopoulos says. “This could be important not only for cancer cells but also other cells growing in hypoxic environments, such as stem cells, placenta and during embryonic development.”

New insights into old models

The researchers are now looking into what other unexpected sources might be diverted into lipid-synthesis pathways under low oxygen. “We had to revise models of metabolism that had been established over the past 50 years. This opens up the possibility for more exciting discoveries in this field that may impact strategies of therapy,” Metallo says.

A better understanding of metabolic pathways and their regulation raises the possibility of developing new drugs that could selectively disrupt key metabolic pathways for cancer cell survival and growth. One possible target is the enzyme isocitrate dehydrogenase, which performs a critical step in the transformation of glutamine to acetyl CoA, a lipid precursor.

“While this target is not new, our findings point to a new function and, hence, generate new ideas for drug development,” Iliopoulos says. “The better we understand the molecular basis of these phenomena, the more optimistic we can be about efforts to translate these basic results into effective treatments of cancer.”

“We’ve been looking, as a field, for almost 90 years for a metabolic pathway that could truly be used to differentiate malignant tumors from normal tissues,” says Ralph DeBerardinis, an assistant professor of pediatrics and genetics at the University of Texas Southwestern Medical Center, who was not involved in this research. He adds that more study is needed, but “if this could be exploited, that could have significant therapeutic potential.”

Mon, 21 Nov 2011 05:00:01 +0000

Seeing cancer in three dimensions
One of the hallmarks of cancer cells is that certain regions of their DNA tend to get duplicated many times, while others are deleted. Often those genetic alterations help the cells become more malignant — making them better able to grow and spread throughout the body.

Now, a team of MIT and Harvard University researchers has found that the three-dimensional structure of the cell’s genetic material, or genome, plays a large role in determining which sections of DNA are most likely to be altered in cancerous cells.

The researchers, led by Leonid Mirny, an associate professor of physics and health sciences and technology, developed a technique to compare the 3-D architecture of chromatin to the chromosomal aberrations often seen in cancer. In the new study, they showed that any two points that routinely encounter each other are more likely to form the end of a DNA loop that gets cut out or duplicated.

“It looks very much like the chromosomal aberrations in cancer, to a large extent, are shaped by the chromosome’s structure,” Mirny says.

The findings, described in the Nov. 20 issue of Nature Biotechnology, reveal mechanisms and underlying physical principles governing genome alterations in cancerous cells, and could help pinpoint locations that host undiscovered cancer-causing or tumor-suppressing genes.

A new dimension

In 2009, a team of scientists — including Mirny and colleagues from MIT, the Broad Institute, the University of Massachusetts Medical School (UMMS), and Harvard — reported the first three-dimensional view of the human genome. Using an experimental technique called Hi-C, developed in the labs of the Broad Institute’s Eric Lander and Andreas Gnirke and UMMS’ Job Dekker, and simulations developed in the Mirny lab, they found that the genome is organized in a structure known as a “fractal globule.” This arrangement enables the cell to pack DNA incredibly tightly while avoiding the knots and tangles that might interfere with the cell's ability to read its own genome.

Mirny and his colleagues had no plans to use Hi-C to study alterations of the genome in cancer until a serendipitous conversation arose with scientists at the Broad Institute. Those researchers, including Gad Getz, the director of Cancer Genome Computational Analysis at the Broad, and Matthew Meyerson, a senior associate member of the Broad and professor of pathology at Harvard Medical School, were studying genetic mishaps —common in cancer cells — known as single copy number alterations (SCNAs).

SCNAs can be deletions of a large region of DNA or duplications of a region — meaning they could play some role in cancer, since it’s advantageous for a cancer cell to have many copies of stretches containing oncogenes (cancer-causing genes), or to delete stretches with tumor-suppressing genes.

Getz and colleagues at the Broad had shown that the probability that a particular stretch of DNA will be duplicated or excised is inversely proportional to its length. When Mirny looked at their findings, he noticed a striking similarity to the Hi-C data: The probability that two particular spots on a chromosome will come into proximity with each other is also inversely proportional to the length of the DNA between them.

Mirny and Getz decided to test the hypothesis that the three-dimensional structure of the chromosome influences the likelihood of a particular stretch of DNA being copied or deleted. To do that, they compared the structure of chromatin predicted by the fractal-globule model with the locations of common SCNAs found in 3,000 cells exhibiting 26 different types of cancer.

What they found confirmed this idea. “What we see by mathematical modeling is that the probability of two points coming together in the 3-D structure is very close to the probability of a loop of that length to be amplified or deleted,” Mirny says.

“It gives even more evidence to the notion that the physical colocation of otherwise disparate regions of the genome in the cell is the source of errors that arise,” says Levi Garraway, an assistant professor of medicine at Harvard Medical School and a member of the Broad Institute and Dana-Farber Cancer Institute who was not involved in this research.

DNA repair gone wrong

This work also suggests a possible mechanism by which SCNAs may occur: When two points are in contact with each other, there is a greater chance that these points may be joined by mistake during DNA repair.

When DNA suffers a break, special enzymes move in to repair it. If two points near each other are being repaired at the same time, the enzymes may accidentally attach them to each other, creating a loop that gets cut out of the genome, says Geoff Fudenberg, a graduate student at Harvard and lead author of the paper.

This explains how excisions might occur, but the researchers believe that the mechanism of creating duplications is likely more complicated.

In this study, the researchers also investigated the likelihood of these alterations spreading through a population of cancer cells. It was already known that alterations beneficial to the cancer cell are more likely to spread through the population, while those that are detrimental get eliminated. There is also a third class of mildly damaging mutations called “passenger mutations.” In this study, the researchers found evidence that these mutations also can be selected against. Specifically, the longer the alteration, the more likely it was to be eliminated.

In future studies, the team plans to analyze 3-D genome models of different cancer types, to see if the alterations likely to occur in liver cancer, for example, differ from those that would occur in lung cancer.

“The more you know about mutational mechanisms, and the more you understand the landscape of possible mutations in cancer, the better job you’re going to do at finding genes that are really helping the cancer, and the better you’ll be able to target those,” Fudenberg says.

Mirny and Fudenberg are members of MIT's Center for Physical Sciences in Oncology, funded by the National Cancer Institute.

Mon, 21 Nov 2011 05:00:00 +0000

MIT senior Stephanie Lin wins Rhodes Scholarship
Stephanie Lin, an MIT senior who is majoring in biology with a minor in applied international studies, has received a Rhodes Scholarship to study next year at Oxford University. She is one of 32 American recipients selected this weekend by the Rhodes Trust.

A native of Irvine, Calif., Lin joins 44 previous MIT recipients who have won the prestigious international scholarships since they were first awarded to Americans in 1904, according to the Institute’s Distinguished Fellowships office.

Lin will pursue an MPhil in medical anthropology at Oxford. She hopes to become an infectious disease physician and epidemiologist, advising governments on effective health care strategies.

Since her freshman year at MIT, Lin has volunteered with Health Leads Boston, a program whose volunteers work with physicians and other health care providers to meet vulnerable families’ needs. After working to educate underprivileged women on the resources available to them for concerns ranging from unemployment to substandard housing, she has become the organization’s resources coordinator, where she advocates for patients and trains and supervises other volunteers.

For the past two years, Lin has been an active member of the MIT Global Poverty Initiative, a student organization dedicated to fighting poverty. In January, she led a trip to La Vaquita, a rural Mexican village, to assess public health there. Her team found, among other things, that lack of protein variation in villagers’ carbohydrate-rich diets was a key contributor to the area’s particularly high rate of deaths due to diabetes. On a subsequent trip to rural Chiteje de Garabeto, Mexico, she led a small pilot project to diversify residents’ diets by building low-cost greenhouses, in conjunction with a local university and the Peace Corps.

During her freshman year, Lin conducted research at the Whitehead Institute for Biomedical Research, studying the Kaposi’s Sarcoma virus, a cancer virus that commonly infects AIDS patients. She built on that work the following two summers at the Chao Cancer Research Center in California, where she studied the pathways by which a retroviral oncogene induces cancer, and at El Instituto de Investigación Biomédica in Barcelona, where she investigated a model organism for mitochondrial diseases.

On campus, Lin has worked in the laboratory of Assistant Professor of Biology Jeroen Saeij, investigating the parasite Toxoplasma gondii and its causation of disease in immunosuppressed patients. This past summer, she interned with the County of San Diego’s Tuberculosis Control Program, where she assessed and improved on a bi-national effort to facilitate continuity of care for tuberculosis patients who travel between the United States and Mexico.

Lin is vice president for education in her sorority, Kappa Alpha Theta; editor-in-chief of MIT’s literary magazine, Rune; and a fluent speaker of Spanish and Mandarin.

“Stephanie’s outgoing personality and humility render her a joy to meet in any language,” says Linn Hobbs, professor of materials science and nuclear science and engineering and chair of MIT’s Presidential Committee on Distinguished Scholarships. “She is a delightful young woman who never fails to greet with a smile and a kind word. Stephanie’s modesty belies a considerable inner strength, amply demonstrated through her volunteer work with some of the most disadvantaged populations both in the U.S. and abroad.”

“MIT is proud of our remarkable class of Rhodes candidates this year, who have learned and benefited from this selection process,” says Kimberly Benard, assistant director of distinguished fellowships in MIT Global Education & Career Development. “These arduous competitions are journeys of self-discovery for every finalist, each of whom is worthy of celebration.”

Sun, 20 Nov 2011 04:44:53 +0000