New tool gives deeper understanding of glioblastoma

Researchers  from Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature Genetics, they identified key switches in different types of tumors, including switches linked to how long a patient survives.

Glioblastoma is an aggressive cancer that forms in the brain or spinal cord. "It's a devastating disease, and there are no good treatment options," said lead author Tinyi Chu, Graduate Fellow, Danko's lab. Even when patients undergo treatment, most survive just 15 months post-diagnosis.

In the new study, Danko's group partnered with colleagues at the State University of New York Upstate Medical University to analyze 20 glioblastoma samples from its tissue bank.

"A lot of diseases, including cancer, fundamentally are defects in how our genes are used, not necessarily in the genes themselves," said Danko, Assistant Professor of Biomedical Sciences. Genes make up only two percent of our genome. Switches called transcription factors bind to the genome to turn those genes on and off, which trigger the cellular changes that cause disease.

To analyze the tumors, the researchers used a technique called ChRO-seq that creates a map of which switches are active and which genes they turn on.

Using ChRO-seq data, the team was able to classify the glioblastomas into subtypes, based on which particular switches were active in the different tumors compared to healthy brain tissues. They also identified three switches that will be tested in larger studies to determine their ability to predict which patients will survive longer with the disease, including two switches whose connections were previously unknown.

Chu is now analyzing an even larger group of glioblastomas to link patient survival and treatment outcomes with the active switches in each tumor. He hopes the results could inform personalized treatment plans for patients or help to develop new therapies in the future.

The new technique studies not only cancer, but many other diseases caused by malfunctions in gene regulation, such as certain types of heart or autoimmune diseases. "ChRO-seq gives you a lot of information about what switch is turning on a tumor or a diseased cell," said Danko. "It gives you a starting point to think about how you can shut that switch off."

 

We welcome researchers from different part of the to submit abstract on their latest research at our upcoming conference Cell Tissue Science 2019 which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more.We welcome you to the our upcoming conference “ 12th World Congress on Cell & Tissue Science” . For more info visit :Cell Tissue Science 2019

Cancer stem cells use normal genes in abnormal ways

CDK1 is a "normal" protein -- its presence drives cells through the cycle of replication. And MHC Class I molecules are "normal" as well -- they present bits of proteins on the surfaces of cells for examination by the immune system. 

But a University of Colorado Cancer Center study published in the Journal Cancer Research shows that a population of cancer cells marked by MHC Class I molecules and high CDK1 is anything but normal. In fact, these MHC Class I-high, CDK1 high molecules may be at the heart of conditions including melanoma, pancreatic and colon cancers. These cells may, in fact, be the long-sought cancer stem cells that often resist treatments like chemotherapy to reseed these cancers once treatment ends.

From the outset, the goal of this study was different than most. Often, cancer researchers will grow tumors and then ask what kinds of drugs or genetic changes make tumors grow or shrink. However, the current study wondered not what makes tumors change size, but what factors in these cells initiate tumor growth in the first place. To answer this question, the study used patient samples, mouse models and publicly available genetic data to search for the genetic/genomic commonalities in cells capable of initiating melanoma, pancreatic and colon cancers.

The findings start with a molecule called MHC Class I, a common molecule that coats the outside of human cells and functions a bit like a hand waving a flag. When MHC Class I molecules wave "flags" (actually bits of proteins), that are not from host tissue, the immune system recognizes the cell as foreign and attacks it. For this reason, most cancer cells downregulate MHC as a way of evading the immune system.

But the current study shows that the population of cancer cells able to initiate the formation of new tumors does not downregulate MHC Class I molecules. In fact, if anything this special population of cancer cells upregulates MHC Class I molecules.

"Probably, these cells have another way to evade the immune system," says Mayumi Fujita, MD, PhD, Investigator at CU Cancer Center and Professor in the CU School of Medicine Departments of Dermatology and Immunology/Microbiology.

Oddly, this population of cancer cells that retains MHC Class I molecules also retains another feature of healthy cells, namely the presence of a protein called CDK1. CDK1 is a master regulator of the cell cycle -- with CDK1, cells progress through the cycle of replication; without CDK1, they do not. In this case, the more CDK1, the more able melanoma cells were to initiate new tumors.

"Our next question was why," Fujita says. "Why would CDK1 control not just the cell cycle, but also stem-ness?"

Finally, the answer includes something that is not "normal." Sox2 is a transcription factor that helps embryonic and neural stem cells keep their stem-ness. It is also a known marker of cancer stem cells, implicated in the development of more than 25 forms of the disease. Despite its identification as a driver of cancer, Sox2 remains a difficult target.

"It's very difficult to control a transcription factor like Sox2. We can show Sox2 is very important for tumorigenesis, but it's difficult to have a Sox2 inhibitor," Fujita says.

However, the current study found that CDK1 directly interacted with Sox2 to keep these cancer cells "stemmy." And here is the important part: "If CDK1 controls Sox2 function through this interaction, probably we can someday inhibit it, maybe through some way of targeting CDK1 or perhaps some way to interfere with the interaction of CDK1 with Sox2," Fujita says.

Importantly, this signature of MHC Class 1, CDK1 and Sox2 was common across melanoma, colon and pancreatic cancers, implying that cancer stem cells across cancer types may share common features.

"We can't say that all tumor types have this signature, but it's prevalent. We think probably this phenotype is very common in melanoma, pancreatic and colon cancer," Fujita says.

Moving forward, the Fujita group hopes to further define the mechanism of Sox2 regulation via CDK1 in hopes of finding essential links that might be targets for new drugs aimed, eventually, at stopping the action of Sox2.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019

Combining genetic and sun exposure data improves skin cancer risk estimates

By combining data on individuals' lifetime sun exposure and their genetics, researchers can generate improved predictions of their risk of skin cancer.

Pierre Fontanillas, PhD, and colleagues at 23andMe, Inc., collected genetic and survey data from over 210,000 consented research participants of European descent. They analyzed the data to identify correlations between previously known and potentially novel skin cancer risk factors and the occurrence of three forms of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Past studies had found that exposure to ultraviolet (UV) light increases skin cancer risk, as do other environmental factors such as living in a sunnier climate or at a higher altitude, and personal factors such as lighter skin pigmentation, higher numbers of moles on the skin, and family history of skin cancer.

"We aimed to validate previously known skin cancer risk factors in a large cohort, add detail to these and explore potential new ones, and find out whether and how these factors might interact with genetic risk," said Dr. Fontanillas.

They found that while each single factor was not particularly significant on its own, multiple factors could be combined into statistical models that were more informative. The best-performing models incorporated a genetic risk score composed of data on up to 50 genetic variants, along with survey data on family history, skin pigmentation and sensitivity, number of moles, estimated current sun exposure, sunbathing frequency before the age of 30, and body mass index (BMI).

The new models achieved a high predictive accuracy (area under the curve [AUC], between 0.81 and 0.85). Genetic factors alone accounted for 8.3 to 15.2 percent of the variance explained in skin cancer risk. Although the three skin cancers have different physiology, models did not find fundamental differences between the three cancer types, nor did they show strong interaction between genetic and environmental risk factors. While the self-reported nature of the survey data permitted researchers to collect a large dataset, it also presented some challenges, Dr. Fontanillas noted.

"Measuring lifetime exposure is generally challenging. It is particularly hard to capture sun exposure and when in life it happened, and it may be that some of the other correlates we found, like higher BMI, reflect a lack of outdoor activity rather than being directly correlated with risk of skin cancer," he said.

Moving forward, the researchers plan to expand their sample to groups with non-European ancestry and are exploring additional methods of calculating genetic risk score and measuring sun exposure. They hope to eventually obtain risk estimates accurate enough to be used by individuals and clinicians.

We welcome researchers from different part of the world to submit your latest research at our upcoming conference "12th World Congress on Cell & Tissue Science" scheduled on March 11-12,2019 in Singapore which is mainly focuses on the complications the consequences of Stem Cell, Regenerative Medicine, Stem Cell Therapy, Cancer Cell Biology , Technical Advancements in cancer treatment and many more. For more info visit our conference website:Cell Tissue Science 2019