The making of a cancer killer, connecting the microbiome and colorectal cancer risk, lung cancer nanosensors, and more
By Broad Communications
Credit: Erik Jacobs
Welcome to the April 3, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
A molecule’s strange switch to cancer killer
Induction of ferroptotic cell death by inhibiting the GPX4 protein could help treat drug-resistant cancer cells. A team of chemical detectives led by Broad founding core member Stuart Schreiber and postdoctoral associates in his lab, Vasanthi Viswanathan and Jake Eaton, in collaboration with scientists at Bayer, revealed the surprising way the “pro-drug” ML210 transforms into a cancer-killing molecule that inhibits GPX4. Described in Nature Chemical Biology, the unusual mechanism sheds light on the process of ferroptosis, and the work could give rise to a new class of drugs that could one day help fight drug-resistant tumors. Read more in a News & Views feature, a Broad news story, and the authors’ tweetorial.
A gut reaction
It’s unclear how the gut microbiome influences risk for colorectal cancer (CRC). A team led by postdoctoral scholar Yan Yan in the Program in Medical and Population Genetics, associate member Andrew Chan at Harvard Medical School and Massachusetts General Hospital, Zsofia Stadler at Memorial Sloan Kettering Cancer Center, and associate member Curtis Huttenhower in the Infectious Disease and Microbiome Program and the Harvard T.H. Chan School Of Public Health analyzed samples from 100 patients with Lynch syndrome, using 16S rRNA gene sequencing of colon biopsies and metagenomic and metatranscriptomic sequencing of feces. As described in Cell Host & Microbe, colectomy with a history of CRC had the biggest effect on the microbiome in these patients. Also, gut microbial changes in Lynch adenoma resemble later stage CRC, and feces metatranscriptome is a weak predictor of future precancerous tumors.
A portal to a musculoskeletal world
Bringing as much data together as possible about a trait or disease can greatly reduce the barriers to genetic discovery. With that in mind, Noël Burtt, Jason Flannick, associate member Douglas Keil in the Program in Medical and Population Genetics, and the Broad's Knowledge Portal team — together with collaborators in International Federation of Musculoskeletal Research Societies — have released the Musculoskeletal Knowledge Portal (MSK-KP). This open-access resource aggregates, integrates, analyzes, and displays ‘omic information on musculoskeletal traits and diseases. The MSK-KP is one of six portals hosted by the Knowledge Portal Network.
Drug Repurposing Hub – new website, compounds, and more
Researchers from the Cancer Program, Center for the Development of Therapeutics, and Connectivity Map project, in partnership with Clue and Pattern teams, have launched the new and updated version of the Drug Repurposing Hub website. The Hub is a unique, open-access repository that now has 6,798 fully annotated compounds, many of which have been FDA approved. The new website features a map to navigate the Hub, a clear “how to conduct a screen” section, videos, and case studies. Despite the wind-down of on-site research activities, the team continues to provide the Repurposing Library, via single concentration assay ready plates, to the worldwide research community to aid COVID-19 studies.
Nanosensors reveal signs of lung cancer in mice
Institute member Sangeeta Bhatia of the Cancer Program and MIT and her colleagues have previously developed a nanoparticle technology that can detect the activity of key proteases associated with cancer in vivo and give a readout of disease in the urine. Now in a study in Science Translational Medicine, Bhatia and her collaborators show that multiplexed nanosensors that are administered into the lungs and look for abnormal protease activity can sensitively reveal the presence of localized lung cancer in two different mouse models of lung adenocarcinoma. The test can also specifically distinguish lung cancer from benign lung inflammation in mice. The results suggest possible clinical development of such nanosensors for lung cancer detection and monitoring.