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PNAS Papers on Sarcoma Fusion Effects, Transfer RNA Changes in Colon Cancer, TB-T2D Interactions

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.

For a paper slated to appear in PNAS this week, University of California, San Francisco, researchers explore the downstream effects of a transcription factor-containing oncoprotein fusion in undifferentiated sarcoma, pointing to potential treatment targets in the aggressive small round cell sarcoma subtype. Using chromatin immunoprecipitation sequencing, the team tracked down hundreds of binding sites involving the CIC-DUX4 oncoprotein fusion in patient-derived cell line experiments, including targets such as the DUSP6 and DUSP4 phosphatase enzymes that negatively regulate MAPK-ERK signaling. That prompted a series of gene silencing experiments to explore the effects of DUSP6 silencing, which appeared to boost MAPK-ERK activation and eventual degradation of the oncoprotein. "Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein," the authors report, "and provide a precision-based strategy to combat this lethal cancer."

A team from Spain and Japan takes a look at the effects of epigenetic alterations affecting transfer RNAs (tRNAs) in colorectal cancer. "[T]he correct hyper-modification of position [guanosine] G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events," the researchers write. With the help of tumor sequence data from the Cancer Genome Atlas project, they searched for DNA methylation changes in a handful of tRNA-related enzymes, narrowing in on promoter hypermethylation changes that dial down levels of the tRNA-yW synthesizing protein 2-coding gene TYW2 in colon cancer and diminish methylation at the phenylalanine-tRNA site tasked with reining in ribosome frameshifts. "[C]ancer cells with the hypomodified guanosine were prone to ribosome frameshifting events," the authors write, adding that "the epigenetic defect in TYW2 was associated with poor clinical outcome" in individuals with early-stage colorectal cancer.

Researchers from Australia, Bangladesh, and France present a tuberculosis (TB) vaccine delivery method that appears to boost TB resistance in mouse models with type 2 diabetes (T2D) — a metabolic condition that can raise TB risk. In a mouse model of diabetes induced through dietary changes, for example, they tracked lung microbiome and gene expression features, comparing them with T2D-free mice to explore potential interactions between TB and T2D and TB vaccine response. "Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D," the team reports, noting that "mucosal delivery of recombinant bacillus Calmette-Guerin strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system …. are safe and confer superior immunity against aerosol Mtb infections in the context of T2D."