Research Roundup: November 20, 2020

Repurposing drugs for COVID, breast cancer through a proteomic lens, roots of liver regrowth, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the November 20, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

From MUC1 to COVID-19 clinical trials

MUC1 normally generates mucus in the lungs, but excess amounts of it have been linked to COVID-19 related lung damage. Maria Alimova, Eriene Sidhom, Kidney Disease Initiative director and institute member Anna Greka, and colleagues reanalyzed data from a previous screen of Drug Repurposing Hub drugs conducted by the Greka lab for MUC1 kidney disease (a rare kidney disorder), and identified an FDA-approved medicine called fostamatinib that blocks the protein. The team showed that the drug reduced MUC1 in human cells and in the lungs of mice suffering from acute lung injury, supporting the rationale for two clinical trials now testing fostamatinib in COVID-19 patients. Read more in Cell Reports Medicine and a Broad story.

SHINE-ing a light on SARS-CoV-2

Jon Arizti Sanz, Catherine Freije, and Cameron Myhrvold — in the Infectious Disease and Microbiome Program (IDMP), the Genomic Center for Infectious Diseases, and the lab of institute member Pardis Sabeti — and colleagues have used the SHERLOCK diagnostic technology to develop a rapid test for COVID-19 called SHINE. The test, which doesn’t require bulky lab equipment and could one day enable SARS-CoV-2 testing outside of hospitals and labs, uses Cas13 to detect SARS-CoV-2 RNA and offers several advantages over the standard qPCR-based test. It reduces the virus inactivation step to 10 minutes, amplifies viral RNA at a stable temperature (eliminating the need for some equipment), and combines amplification and detection into a single step. Read more in Nature Communications and a Broad story

A new view on breast cancer

Breast cancer is a diverse disease, making it challenging for doctors and scientists to tailor promising treatment combinations for patients. Working with the NCI's Clinical Proteomics Tumor Analysis Consortium (CPTAC), Karsten Krug, Shankha Satpathy, DR Mani, institute scientist Steven Carr, and Michael Gillette of the Proteomics Platform, together with colleagues at Baylor College of Medicine and elsewhere, conducted comprehensive proteomic and genomic — or proteogenomic — profiling of a large set of breast tumors. Their findings, published in Cell, highlight new tumor subtypes, metabolic vulnerabilities, immunotherapy opportunities, and more, and suggest a role for proteogenomics in cancer diagnosis and treatment planning. Learn more in a Broad/Baylor/CPTAC press release.

A deep dig detects differences

Germline genetic analysis using standard methods can identify rare pathogenic variants in a small fraction of cancer patients. A team led by postdoctoral scholar Saud AlDubayan and associate member Eliezer Van Allen of Dana-Farber Cancer Institute and the Cancer Program analyzed germline data from thousands of patients with prostate cancer or melanoma, first using a standard approach and then with DeepVariant, a deep neural network analysis framework. They found that deep learning significantly enhanced the ability to discover informative germline variants in thousands of cancer-predisposition and other clinically relevant genes. Learn more in a Dana-Farber video, a tweetorial, and in JAMA

Microbiome metagenomes

Cultivation-independent approaches to studying microbial CRISPR systems, such as metagenomics, can reveal unexplored CRISPR system diversity. A team led by associated researcher Philipp Münch, Alice McHardy of the Helmholtz Center for Infection Research, and IDMP associate member Curtis Huttenhower of the Harvard T.H. Chan School of Public Health profiled CRISPR loci and cas genes in the body-wide human microbiome using 2,355 metagenomes. The scientists identified nearly 3 million unique CRISPR spacers, increasing the known diversity by 13-fold, with oral habitats showing higher CRISPR load than gut/urogenital sites. Described in Cell Host & Microbe, the work provides a map of natural CRISPR-cas loci and targets in the human microbiome.

Build 'em up, break 'em down

Targeted degradation, where a small molecule tricks a cancer cell into trashing a protein that it relies on to survive, is a promising approach for attacking a variety of cancer targets. In Nature,  researchers from the Cancer Program and Dana-Farber including Mikolaj Slabicki, Hojong Yoon, Jonas Koeppel, institute member Benjamin Ebert, and Eric Fischer discuss a new mechanism for triggering protein degradation, wherein a compound induces its target to form polymers that are subsequently degraded by a cellular disposal system. This animation shows how a compound called BI-3802 employs this drug-induced polymerization mechanism to rid cells of BCL6, a lymphoma-linked transcription factor.

How the liver bounces back

The liver possesses an incredible ability to regenerate following injury. However, it must still maintain vital functions while this process is ongoing. Using single-cell RNA sequencing, in situ transcriptional and proteomic analyses, and knockout models in mice, Chad Walesky (BWH), Kellie Kolb (MIT), institute member Alex Shalek, Metabolism Program associate member Wolfram Goessling, and colleagues have uncovered the mechanisms enabling this continued function. Cells remaining in the liver after injury temporarily ramp up expression of key genes and alter their normal zone-specific functions to compensate for the lost cells, while other cells within the liver control new tissue growth. Read the full story in Nature Communications.

Above AvG 

In mass spectrometry, data-independent acquisition (DIA) has the potential to comprehensively analyze all peptides in a biological sample that are above an instrument’s limit of detection. However, several challenges remain in DIA data analysis, and each analysis tool shows variability in detectable peptides and quantitative results. To address these variabilities, research scientist Sebastian Vaca, Steven Carr, Proteomics Platform visiting scientist Jacob Jaffe (Inzen Therapeutics), and others designed Avant-garde (AvG), a modular tool for polishing DIA data. In Nature Methods, they report that AvG refined DIA signals to reach the highest possible levels of sensitivity, selectivity, and accuracy.

Aneuploidy protects cancer cells

Cancer cells often possess abnormal numbers of chromosomes, a condition called aneuploidy. Aneuploidy is paradoxically associated with both slower proliferation of cells and poor patient prognosis in many cancer types. A team led by John Michael Replogle (MIT), associate member Angelika Amon, and colleagues investigated the underlying mechanisms of these observations, and found that aneuploidy’s effects on cell division actually increased resistance to frontline chemotherapeutics: slowing proliferation down reduced the drugs' ability to damage cancer cells' DNA and microtubules. Learn more in PNAS.

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