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News / 01.25.19

Research Roundup: January 25, 2019

Erik Jacobs
Credit : Erik Jacobs
By Broad Communications

Circulating tumor cells captured, another CRISPR enzyme harnessed, a rare bone tumor's vulnerabilities probed, and more.

Welcome to the January 25, 2019 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

CTCs go with the flow

Using mouse models to study the role of circulating tumor cells (CTCs) in cancer is difficult because the cells are rare and blood volume is low. In PNAS, senior associate member Tyler Jacks and associate members Alexander Shalek and Scott Manalis describe an optofluidic system, developed in part by Sanjay Prakadan and MIT's Bashar Hamza and Sheng Rong Ng, that collects labeled CTCs from a mouse model over days or weeks. Blood flows through a microfluidic cell sorting chip, where CTCs are captured, before returning to the animal. The approach eliminates biases from collecting CTCs across different mice and can help reveal how CTCs evolve over time.

Putting lipid metabolism to the (fatty) acid test

In Cell Metabolism, institute scientist and Metabolomics Platform director Clary Clish, associate member Eugene Rhee, Massachusetts General Hospital's Wondong Kim, institute member and Metabolism Program co-director Jose Florez, and Diabetes Research Group associate scientific director Suzanne Jacobs describe their efforts to shed light on lipid metabolism and the role of polyunsaturated fatty acid desaturation. The researchers found that highly unsaturated fatty acid (HUFA) synthesis is a mechanism for glycolytic NAD+ recycling that operates in parallel with lactate fermentation. The results help explain how variants in SLC16A11, a gene implicated in type 2 diabetes, could impact cellular HUFA production and contribute to the disease. They also provide insight on human genetic studies that link HUFA desaturation with various phenotypes.

New CRISPR system harnessed for better genome editing

In Nature Communications, core institute member Feng Zhang and postdoctoral fellow Jonathan Strecker, along with colleagues at Broad, the McGovern Institute for Brain Research at MIT, and the National Institutes of Health, reported on a new CRISPR enzyme, Cas12b, that can be engineered to target and precisely nick or edit the genomes of human cells. Compared to previous systems, Cas12b, which the team had derived from Bacillus hisashii (BhCas12b), offers improved capabilities, including a relatively high target specificity and small size, that make it better suited for many in vivo applications. Read more in a Broad news story.

A gut gene behind IBD's microbial remix

Variants in more than 230 parts of the genome are involved in inflammatory bowel disease risk. A team led by associate member Wendy Garrett, core institute member and Infectious Disease and Microbiome Program co-director Ramnik Xavier, and Joslin Diabetes Center's Alexander Kostic describe how one variant, ATG16L1 T300A, raises that risk. The team found that, in mice, this variant affects both the gut microbiome's composition and the balance of immune activity in the gut. Interestingly, these gut changes emerge before signs of IBD appear, and suggest that the microbial differences may remodel the immune response. Read the full report in eLife.

Rare bone tumor opens up about its vulnerabilities

Beyond surgery and radiation, the treatment options for patients with chordoma — a rare cancer of the spine, skull base, or tailbone — are slim. A team led by Tanaz Sharifnia and core institute member Stuart Schreiber of the Chemical Biology and Therapeutics Science Program partnered with the Chordoma Foundation and chordoma patients to run the first systematic screens of the tumor's genetic dependencies (genes it relies on to survive, and which represent possible vulnerabilities). Their data, reported in Nature Medicine, confirmed that the tumor's defining feature (overexpression of a transcription factor called brachyury) is also its top dependency, and revealed a promising path to treatment. Read more in a Broad news story.

Checking on CHEK2 for testicular cancer

Testicular germ cell tumors (TGCTs) are highly heritable and malignant tumors which affect young males. Irrespective of its high heritability, researchers were not able to identify genes predisposed to Mendelian forms of testicular cancer in the past. A team led by Cancer Program associate member Eliezer Van Allen, Saud AlDubayan, and colleagues set out to investigate if inherited pathogenic mutations in DNA repair genes increase susceptibility to TGCTs. Studying a cohort of 884 male adults, the team confirmed that inherited pathogenic mutations in a tumor suppressor gene called CHEK2 increased the risk of testicular cancer up to six times. Read more in JAMA Oncology.

CREating an atlas of the mouse immune system

Few research efforts in the past have looked into pairing epigenomic measurements with transcriptomic measurements, thus limiting the understanding of how epigenomic changes influence gene expression. By pairing the two assays, ATAC-seq (for epigenomic profiling) and RNA-seq (for transcriptomic profiling), associate member Jason Buenrostro, Caleb Lareau, and collaborators built an atlas of 512,595 cis-regulatory elements (CREs) active in 86 cell types of the mouse immune system. CREs are regions of non-coding DNA which regulate the transcription of neighboring genes. This detailed CRE map and breadth of data, published in Cell, will allow the research community to gather improved insights on gene expression patterns in immune cells and disease.

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