January 3, 2019 | Tom Wilemon
Glutamine metabolism affects T cell signaling & function
The cellular nutrient glutamine launches a metabolic signaling pathway that promotes the function of some immune system T cells and suppresses others, Vanderbilt researchers have discovered. They show that a drug that inhibits glutamine metabolism — currently in clinical trials as an anticancer agent — might also be useful as a treatment for inflammatory and autoimmune diseases. The study, published online Nov. 1, 2018, in the journal Cell, also suggests strategies for using the drug to enhance cancer immunotherapies. Jeffrey Rathmell, PhD, and colleagues have focused on trying to understand how a cell integrates its nutrients and metabolism with its function. They previously demonstrated the importance of the cellular fuel glucose for the activation and function of T cells that drive inflammation and eliminate pathogens. In the current work, they turned their attention to another major fuel: glutamine, which has primarily been studied in the context of cancer cell metabolism.
Connecting an asthma gene to leukemia
A receptor previously implicated in asthma called ST2 may also play roles in other allergic diseases and in leukemia, Vanderbilt researchers have discovered. The investigators, led by Melissa Bloodworth, PhD, and Mark Rusznak, performed a phenome-wide association study (PheWAS) to search for associations between known variants in the ST2 gene and diagnoses in medical records. The researchers found that specific ST2 variants associated with other allergic conditions, and they confirmed associations with asthma. They also uncovered a novel association of two ST2 variants with forms of leukemia. The findings, reported May 19, 2018, in Journal of Allergy and Clinical Immunology, establish the first genetic link between ST2 and leukemia.
New breast cancer targets
Genome-wide association studies (GWAS) have identified more than 150 genetic variations associated with increased risk for breast cancer. Most of these variants are not located in protein-coding gene regions but are assumed to regulate the expression of certain genes. Using four large-scale data sets from normal and cancerous breast tissue samples, Xingyi Guo, PhD, and colleagues identified 101 candidate breast cancer susceptibility genes with variant-associated gene expression changes. In breast cancer cells grown in culture, the researchers also demonstrated how three genes promoted tumor growth by disrupting normal cell behavior. The findings, published May 3, 2018, in the American Journal of Human Genetics, reveal potential target genes associated with an increased risk of breast cancer and provide additional insights into the underlying genetic and biological mechanisms that drive this common cancer.
Studying cellular deliveries
Many cells, including cancer cells, are known to secrete short RNAs in tiny vesicles, which then move inside other cells – potentially a form of cell-to-cell communication. In an article published Oct. 18, 2018, in Cell Reports, James Patton, PhD, and colleagues studied how colon cancer cells secrete long RNAs in carefully regulated ways.
Using light to fight GVHD
Extracorporeal photopheresis (ECP) is used to treat chronic graft-versus-host disease (cGVHD) – a complication of bone marrow or stem cell transplant that occurs when donor cells attack the recipient. How ECP works is unclear, and standardized treatment guidelines have not been established. Vanderbilt medical student Jocelyn Gandelman, Madan Jagasia, MBBS, and colleagues conducted a prospective, multicenter clinical trial of ECP for cGVHD. They found that in a highly pretreated group of patients, 62.3 percent had a provider-assessed response to ECP and 43.5 percent had a response according to National Institutes of Health consensus guidelines. The findings, reported July 5, 2018, in Biology of Bone and Marrow Transplantation, support further study of ECP therapy.
“Idling” cancer cells may return
About half of all melanomas have mutations in the BRAF gene that accelerate tumor cell growth and spread. While most patients benefit from targeted anti-BRAF therapy, resistance to treatment and tumor progression is almost inevitable. Vito Quaranta, MD, and colleagues studied the response of several BRAF-mutated melanoma cell lines to BRAF inhibitors. Reporting March 27, 2018, in Biophysical Journal, they found that treated cells entered a previously unrecognized “idling” state in which the number of dividing cells matched the number of dying cells.
SMAD4 clue to colon cancer
Chronic inflammation is a predisposing condition for colorectal cancer, the third leading cause of cancer-related deaths in the United States. Reporting in June 2018 in Cellular and Molecular Gastroenterology and Hepatology, Anna Means, PhD, and colleagues have now linked inflammation-driven carcinogenesis in the colon to loss of an important signaling protein called SMAD4. This protein is part of the transforming growth factor beta (TGF-beta) signaling pathway in the epithelium of the colon that regulates the immune/inflammatory response to infection.
Transporter protein’s role in lung cancer
Xiangming Ji, PhD, Pierre Massion, MD, and colleagues studied the role of the transporter protein xCT in non-small cell lung cancer (NSCLC). They demonstrated that xCT was highly expressed at the cell surface in NSCLC tumors and that elevated xCT correlated with advanced stage cancer and worse five-year survival in patients. Their findings reported May 23, 2018, in Oncogene indicated that blocking xCT transport activity with the drug sulfasalazine decreased cell proliferation and invasion in cell and animal models.
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