Nature Genetics

Flip the Switch

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Changes in fat metabolism may promote prostate cancer metastasis

Prostate tumors tend to be what scientists call “indolent”—so slow-growing and self-contained that many affected men die with prostate cancer, not of it. But for the percentage of men whose prostate tumors metastasize, the disease is invariably fatal.

In a set of papers published in the journals Nature Genetics and Nature Communications, researchers at Harvard Medical School and the Cancer Center at Beth Israel Deaconess Medical Center have shed new light on the genetic mechanisms that promote metastasis in a mouse model and implicated the typical Western high-fat diet as a key environmental factor driving metastasis.

“Although it is widely postulated that a Western diet can promote prostate cancer progression, direct evidence supporting a strong association between dietary lipids and prostate cancer has been lacking,” said first author Ming Chen, HMS research fellow in medicine in the laboratory of Pier Paolo Pandolfi, the HMS George C. Reisman Professor of Medicine at Beth Israel Deaconess.

Epidemiological data links dietary fats (and obesity) to many types of cancer, and rates of cancer deaths from metastatic cancers including prostate cancer are much higher in the United States than in nations where lower fat diets are more common. While prostate cancer affects about 10 percent of men in Asian nations, that rate climbs to about 40 percent when they immigrate to the U.S., mirroring the rates among the native-born U.S. population. That points to an environmental culprit that may work in concert with genetic factors to drive this aggressive, fatal disease.

“The progression of cancer to the metastatic stage represents a pivotal event that influences patient outcomes and the therapeutic options available to patients,” said senior author Pandolfi, who is also director of the Cancer Center and the Cancer Research Institute at Beth Israel Deaconess. “Our data provide a strong genetic foundation for the mechanisms underlying metastatic progression, and we also demonstrated how environmental factors can boost these mechanisms to promote progression from primary to advanced metastatic cancer.”

The tumor suppressor gene PTEN is known to play a major role in prostate cancer; its partial loss occurs in up to 70 percent of primary prostate tumors. Its complete loss is linked to metastatic prostate disease, but animal studies suggest the loss of PTEN alone is not enough to trigger progression. Pandolfi and colleagues sought to identify an additional tumor suppressing gene or pathway that may work in concert with PTEN to drive metastasis.

Looking at recent genomic data, Pandolfi and colleagues noticed that another tumor suppressor gene, PML, tended to be present in localized (nonmetastatic) prostate tumors but was absent in about a third of metastatic prostate tumors. Moreover, about 20 percent of metastatic prostate tumors lack both PML and PTEN.

When they compared the two types of tumor—the localized ones lacking only the PTEN gene versus the metastatic tumors lacking both genes—the researchers found that the metastatic tumors produced huge amounts of lipids, or fats. In tumors that lacked both PTEN and PML tumor suppressing genes, the cells’ fat-production machinery was running amok.

“It was as though we’d found the tumors’ lipogenic, or fat production, switch,” said Pandolfi. “The implication is, if there’s a switch, maybe there’s a drug with which we can block this switch and maybe we can prevent metastasis or even cure metastatic prostate cancer,” he added.

Such a drug already exists. Discovered in 2009, a molecule named “fatostatin” is currently being investigated for the treatment of obesity. Pandolfi and colleagues tested the molecule in lab mice. “The obesity drug blocked the lipogenesis fantastically, and the tumors regressed and didn’t metastasize.”

In addition to opening the door to new treatment for metastatic prostate cancer, these findings also helped solve a long-standing scientific puzzle. For years, researchers had difficulty modeling metastatic prostate cancer in mice, making it hard to study the disease in the lab. Some speculated that mice simply weren’t a good model for this particular disease. But the lipid-production finding raised a question in Pandolfi’s mind.

“I asked, ‘What do our mice eat?’” Pandolfi recalled.

It turned out the mice ate a vegetable-based chow, essentially a low-fat vegan diet that bore little resemblance to that of the average American male. When Pandolfi and colleagues increased the levels of saturated fats, the kind found in fast food cheeseburgers and fries, in the animals’ diet, the mice developed aggressive, metastatic tumors.

The findings could result in more accurate and predictive mouse models for metastatic prostate cancer, which in turn could accelerate discovery of better therapies for the disease. Additionally, physicians could soon be able to screen their early-stage prostate cancer patients for those whose tumors lack both PTEN and PML tumor suppressing genes, putting them at increased risk for progressing to metastatic disease. These patients may be helped by starving these tumors of fat either with the fat-blocking drug or through diet.

“The data are tremendously actionable, and they surely will convince you to change your lifestyle,” Pandolfi said.

NIH-supported study identifies 11 new Alzheimer’s disease risk genes.

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An international group of researchers has identified 11 new genes that offer important new insights into the disease pathways involved in Alzheimer’s disease. The highly collaborative effort involved scanning the DNA of over 74,000 volunteers—the largest genetic analysis yet conducted in Alzheimer’s research—to discover new genetic risk factors linked to late-onset Alzheimer’s disease, the most common form of the disorder.

By confirming or suggesting new processes that may influence Alzheimer’s disease development—such as inflammation and synaptic function—the findings point to possible targets for the development of drugs aimed directly at prevention or delaying disease progression.

Supported in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, the International Genomic Alzheimer’s Project (IGAP) reported its findings online in Nature Genetics on Oct. 27, 2013. IGAP is comprised of four consortia in the United States and Europe which have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting the subtle gene variants involved in Alzheimer’s and defining how the molecular mechanisms influence disease onset and progression.

“Collaboration among researchers is key to discerning the genetic factors contributing to the risk of developing Alzheimer’s disease,” said Richard J. Hodes, M.D., director of the NIA. “We are tremendously encouraged by the speed and scientific rigor with which IGAP and other genetic consortia are advancing our understanding.”

The search for late-onset Alzheimer’s risk factor genes had taken considerable time, until the development of GWAS and other techniques. Until 2009, only one gene variant, Apolipoprotein E-e4 (APOE-e4), had been identified as a known risk factor. Since then, prior to today’s discovery, the list of known gene risk factors had grown to include other players—PICALM, CLU, CR1, BIN1, MS4A, CD2AP, EPHA1, ABCA7, SORL1 and TREM2.

IGAP’s discovery reported today of 11 new genes strengthens evidence about the involvement of certain pathways in the disease, such as the role of the SORL1 gene in the abnormal accumulation of amyloid protein in the brain, , a hallmark of Alzheimer’s disease. It also offers new gene risk factors that may influence several cell functions, to include the ability of microglial cells to respond to inflammation.

The researchers identified the new genes by analyzing previously studied and newly collected DNA data from 74,076 older volunteers with Alzheimer’s and those free of the disorder from 15 countries. The new genes (HLA-DRB5/HLA0DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2 and CASS4) add to a growing list of gene variants associated with onset and progression of late-onset Alzheimer’s. Researchers will continue to explore the roles played by these genes, to include:

·         How SORL1 and CASS4 influence amyloid, and how CASS4 and FERMT2 affect tau, another protein hallmark of Alzheimer’s disease

·         How inflammation is influenced by HLA-DRB5/DRB1, INPP5D, MEF2C, CR1 and TREM2

·         How SORL1affects lipid transport and endocytosis (or protein sorting within cells)

·         How MEF2C and PTK2B influence synaptic function in the hippocampus, a brain region important to learning and memory

·         How CASS4, CELF1, NME8 and INPP5 affect brain cell function

The study also brought to light another 13 variants that merit further analysis.

“Interestingly, we found that several of these newly identified genes are implicated in a number of pathways,” said Gerard Schellenberg, Ph.D., University of Pennsylvania School of Medicine, Philadelphia, who directs one of the major IGAP consortia. “Alzheimer’s is a complex disorder, and more study is needed to determine the relative role each of these genetic factors may play. I look forward to our continued collaboration to find out more about these—and perhaps other—genes.”

Schellenberg heads the Alzheimer’s Disease Genetics Consortium (ADGC), one of the four founding partners of IGAP. The ADGC is a collaborative body established and funded by the NIA with the goal of identifying genetic variants associated with risk for Alzheimer’s. Schellenberg noted that the study was made possible by the research infrastructures established and supported by the NIA over many years, including 29 Alzheimer’s Disease Centers, the National Alzheimer’s Coordinating Center, the NIA Genetics of Alzheimer’s Disease Data Storage Site, the Late-onset Alzheimer’s Disease Family Study, and the National Cell Repository for Alzheimer’s Disease. These endeavors collect, store and make available to qualified researchers DNA samples, datasets containing biomedical and demographic information about participants, and genetic analysis data.

Rice gene digs deep to triple yields in drought.

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A gene that gives rice plants deeper roots can triple yields during droughts, according to Japanese researchers writing in Nature Geneticsthis week (4 August).

Rice is a staple food for nearly half of the world’s population, but is also particularly susceptible to drought owing to its shallow roots, researchers say.

“If rice adapts to or avoids drought conditions using deeper roots, it can get water and nutrients from the deep soil layers.”

Yusaku Uga

The new study shows that by pointing roots down instead of sideways, the Deeper Rooting 1(DRO1) gene results in roots that are nearly twice as deep as those of standard rice varieties.

“If rice adapts to or avoids drought conditions using deeper roots, it can get water and nutrients from the deep soil layers,” says the study’s lead author Yusaku Uga, a researcher with Japan’s National Institute of Agrobiological Sciences.

Uga and his team found that in moderate drought conditions, the yield of rice with DRO1 was double that of the shallow-rooted rice variety. Under severe drought conditions, this increased to 3.6 times greater.

“The most important point is that we had rice grains produced under drought conditions,” says Uga. “When rice crops just tolerate drought, they cannot get water and nutrients, resulting in a kind of survival mode.”

The DRO1 gene occurs naturally in more than 60 rice varieties. For the study, the research team crossbred a rice variety carrying DRO1 with a shallow-rooted variety and then bred the offspring together to produce a rice crop in which DRO1 was uniformly present.

The International Rice Research Institute (IRRI) estimates that an additional 8-10 million tonnes of rice will be needed each year to keep rice prices affordable at around US$300 per tonne. Finding a drought-resistant variety of rice may be key to attaining this goal, according to researchers.

“Drought is the most widespread and damaging of all environmentalstresses,” says Sophie Clayton, head of communications at IRRI. “In some states in India, severe drought can cause as much as 40 per cent yield loss [in rice crops]. Moreover, with the onset of climate change, droughts may become more frequent and more severe.”

Source: Scivx