Using a microRNA to Shift the Makeup of Glioblastoma Subtypes

Glioblastoma multiforme (GBM), an extremely aggressive brain cancer, is a very complex disease. It is characterized by a fast-growing tumor in the brain composed of many subpopulations of cells, including glioblastoma stem cells, which play a crucial role in glioblastoma initiation, expansion and therapy-resistance. GBM’s diverse make up – termed heterogeneity – is of clinical importance because it is a key factor that leads to treatment failure, allowing the tumor to become resistant to treatment or for cancer to recur.

One way to identify different glioblastoma subtypes is by looking at the specific microRNA expressed in the patient derived GBM stem cells. In several types of cancer cells, including glioblastoma cells, microRNA expression isn’t regulated properly. In a new study published in Cell Reports, BWH researchers examined a specific microRNA, miR-128, to help identify glioblastoma subtypes and to determine if altering the microRNA’s presence in glioblastoma cells could change the tumor’s subtype.

“RNA is increasingly recognized as a snapshot of a cell at a given moment in time and therefore gives unique insight into the disease biology,” said lead author Arun Kumar Rooj, PhD, of the Department of Neurosurgery at BWH. “Understanding the dynamic spectrum of cells and their non-coding RNA signatures is critical for advancing therapeutic strategies that will be capable of overcoming the complexity of this disease.”

The researchers looked at miR-128 expression in diverse populations of glioblastoma cells. They identified the “proneural” subtype as having high levels of miR-128 compared to the mesenchymal tumors, which had significantly lower levels of this particular microRNA. Interestingly, they also found that if they raised or lowered the levels of miR-128, they could induce one subtype of tumor to transition into a new subtype.

“Mesenchymal glioblastoma is extremely aggressive, highly heterogeneous and has the poorest chance of survival for patients,” said corresponding author Agnieszka Bronisz, PhD, of the BWH Department of Neurosurgery. “By altering the level of miR-128 in both mesenchymal and proneural tumors, we can shift the tumor into a more hybrid type, similar to the “classical” subtype which is more homogenous and easier to treat.”

“The ability to transform more aggressive types of glioblastoma into a subtype that is more responsive to treatment opens the door for using miR-128 as a therapeutic agent,” said corresponding author Jakub Godlewski, PhD, of the BWH Department of Neurosurgery.

This work was funded by the National Cancer Institute (grant numbers P01 CA69246 and R01 CA 176203-01A1).

Paper cited: Rooj AK et al. “MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells” Cell Reports DOI:10.1016/j.celrep.2017.05.040

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Socioeconomic Stress During Pregnancy Impacts Infant Brain Development

Children born into socioeconomically disadvantaged homes face higher risks of disease and health disorders throughout their lives. In fact, economic disparities can impact children’s future health before they are even born. The impact of social environment on a baby’s brain development is not fully understood, but new research led by investigators at BWH and the National Institute of Child Health and Development provides evidence that this connection is, in part, impacted by the mother’s immune response during pregnancy. Their findings are published this week in the Proceedings of the National Academy of Sciences.

Pregnancy can be a stressful time, especially for those under chronic financial and social strain. When an expectant mother is under chronic stress, her body’s immune system creates a physiological response that can influence fetal development. To understand how the mother’s immune system during pregnancy might influence neurodevelopment in a child’s early life, researchers examined the inflammatory response to chronic social adversity in 1,494 participants from the New England Family Study.

The researchers measured the concentrations of specific inflammatory chemicals, called cytokines, in maternal sera collected from women in their third trimester. They found that the most socioeconomically disadvantaged women had lower levels of interleukin-8 (IL-8), a pro-inflammatory cytokine. When stressed, the body produces “stress hormones” (glucocorticoids) that reduce the body’s inflammatory response. Chronic socioeconomic stress during pregnancy and the associated production of glucocorticoids may, in part, explain the decreased levels of IL-8.

This immune response can also impact a child’s brain development. In this study, decreased fetal exposure to IL-8 was significantly associated with neurologic abnormalities during infancy. Researchers found that children born to mothers with the largest socioeconomic disadvantage were 4.6 times more likely to have neurologic abnormalities at age 4 months and two times more likely to have these abnormalities at 1 year compared to the children of less disadvantaged mothers.

“The impact of social inequalities on health outcomes have early origins that may be retained throughout life,” said Jill Goldstein, PhD, Chair of the Brigham Research Institute Center for Research on Women’s Health and Gender Biology and senior author of the study. “Chronic socioeconomic stress during pregnancy, and the immune response that follows, can contribute to vulnerabilities later in life for offspring.”

However, Goldstein cautions that children born into poverty are not destined to experience more health problems. It is important to identify high risk children, which could result in intervening early to promote cognitive and emotional health.

This work was funded by the Office for Research on Women’s Health, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Paper cited: Gilman, S et al. “Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.” PNAS DOI: 10.1073/pnas.1617698114

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Understanding HIV’s Persistence

Most cells in the human body have a limited lifespan, typically dying after several days or weeks. And yet, HIV-1 infected cells manage to persist in the body for decades. Current treatment for HIV is very effective at suppressing the virus, but is unable to entirely clear the disease, which can rapidly recur if treatment is ever stopped. A new study, published in the Journal of Clinical Investigation, led by Mathias Lichterfeld, MD, PhD, and Guinevere Lee, PhD, from the BWH Infectious Disease Division sheds new light on the mechanism underlying the persistence of HIV-1 infected cells despite antiviral treatment.

“Our research points to a driving force that stabilizes the pool of HIV-infected cells in the host, which can persist lifelong despite very effective antiretroviral therapy,” said Lichterfeld. “These findings have important implications for efforts to reduce or eliminate HIV from the body, including interventions like vaccines and checkpoint inhibitors.”

Using a novel viral sequencing approach to track viral infection in different subtypes of CD4 T cells, this study found that a remarkable number of infected cells harbor sequences that are completely identical over the entire full-length viral sequence. Indeed, individual clusters of cells harboring such identical sequences were observed in roughly 60 percent of all memory CD4 T cells, the primary target cells for HIV. These data suggest that cells harboring identical viral sequences all stem from one particular CD4 T cell that presumably got infected prior to the beginning of antiviral therapy. That cell has gone on to disseminate and expand the HIV-infected cell pool whenever it divides, passing on the viral genetic material to its daughter cells in a process called “clonal proliferation.” By this mechanism, a single HIV-infected cell can, simply by dividing for 10-20 times, amplify the number of virally infected cells by up to a million fold.

“This work shows that HIV is taking a free ride: It effectively exploits the normal proliferative behavior of human cells for propagation and dissemination of the viral genome,” said Lee.

Interrupting or blocking proliferation of such virally-infected cells may represent a future strategy to limit viral persistence despite treatment, and may someday allow for the development of novel clinical interventions, leading to a long-term, drug-free remission of HIV infection.

Funding for this work was provided by the National Institutes of Health (grants AI098487, AI106468, AI114235, AI117841, AI120008, AI124776, AI116228, AI078799, HL134539, R3767073), the AIDS Vaccine Discovery from the Bill and Melinda Gates Foundation, the International AIDS Vaccine Initiative, the NIH-funded Harvard University Center for AIDS Research (grant P30 AI060354) which is supported by the following NIH co-funding and participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR.

Paper cited: Lee GQ et al. “Clonal expansion of genome-intact HIV-1 in functionally-polarized Th1 CD4 T cells.” Journal of Clinical Investigation DOI: 10.1172/JCI93289

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