Research Roundup: April 23, 2021

A new neuroblastoma target, a search for radiation-related biomarkers in cancer, profiling neurons' interactions, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the April 23, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Pediatric DepMap yields promising drug target

Researchers recently built a map of genetic dependencies for pediatric cancers. Now postdoctoral fellow Clare Malone, Cancer Dependency Map scientific director Francisca Vazquez, institute member Kim Stegmaier (Dana-Farber Cancer Institute), and colleagues with the Cancer DepMap team and the Genetic Perturbation Platform have used that map to find one such dependency, NXT1, for a common type of childhood tumor, neuroblastoma. They report that the gene is a promising drug target for some forms of neuroblastoma. Depleting NXT1 in these cancer cells results in the loss of another gene, called NXF1, which is essential for cell survival. Drugs that block NXT1 could selectively kill neuroblastoma cells compared to normal cells. The team is working with colleagues in the Center for the Development of Therapeutics to look for small molecules that could inhibit NXT1. Learn more in Cancer Discovery and a Broad story.

Surveying the genomic landscape of radiation-related cancers

Radiation exposure is a well-known risk factor for cancer, but researchers are still searching for molecular and genetic features associated with radiation dose. An international team led by Chip Stewart and Gad Getz, director of cancer genome computational analysis; Gerry Thomas (Imperial College London); Mykola Tronko (National Academy of Medical Sciences of Ukraine); and Lindsay Morton, Danielle Karyadi, and Stephen Chanock (National Cancer Institute; NCI) analyzed whole genomes and transcriptomes from 359 thyroid cancers associated with the 1986 Chernobyl accident. The team noted a relationship between radiation dose and the burden of DNA double strand break-related gene fusions, especially in the MAPK pathway, but did not find any unique radiation-related biomarkers. Learn more in Science and an NCI press release.

A RABID sequencing method for understanding neuronal disease 

Cells interact with each other to control physiology and pathology of the central nervous system (CNS). However, current approaches that can profile individual cells in the CNS are unable to profile cell interactions or may fail to detect interactions involving only a small subset of cells. Iain Clark (Brigham and Women’s Hospital), Cristina Gutiérrez-Vázquez (BWH), Michael Wheeler of the Metabolomics Platform, associate member Francisco Quintana of the Immunology Program, and colleagues developed a novel virus-based method called RABID-seq to barcode cell interactions at single cell resolution in vivo. With RABID-Seq researchers uncovered novel physiological mechanisms and candidate therapeutic targets associated with neuronal disorders such as autoimmune encephalomyelitis and multiple sclerosis. This method can be applied to other neurologic diseases and study cell interactions outside the CNS. Read more in Science.

Charge filtering on gasdermin D pores governs release of IL-1

Gasdermin proteins are implicated in cancers and inflammatory diseases and display potential as therapeutic targets. When cleaved by inflammatory caspases, gasdermin D (GSDMD) forms transmembrane pores that release IL-1 cytokines and mediate forms of programmed cell death. Despite their importance, little is known about the formation and structure of GSDMD pores. In Nature, associate member Hao Wu (associate member, Chemical Biology and Therapeutics Science Program), Shiyu Xia (Boston Children’s Hospital, Harvard Medical School), Anna Greka (institute member, Kidney Disease Initiative), and colleagues report cryoEM structures of the GSDMD pore and prepore showing that the pore conduit of GSDMD is negatively charged. They further illustrate release of cytokines in liposomes and macrophages with GSDMD pores, showing that the channels mediate release of IL-1 with electrostatic filtering.

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