Research Roundup: July 16, 2021

Tracking cancer clones, developing diagnostic nanosensors, when is pleiotropy not pleiotropy, and more

Welcome to the July 16, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Clonal cartography

Methods for tracing cell subtypes' or clones' evolution within a tumor generally don't combine -omic measurements and live-cell experimental data into a comprehensive view. Writing in Nature Cancer, Catherine Gutierrez, Aziz Al’Khafaji, institute member Catherine Wu of the Cancer Program, and colleagues present the multifunctional lineage tracing tool ClonMapper, which employs DNA barcoding, single-cell RNA sequencing, and clonal isolation to examine thousands of cancer cell clones within a mixed population. They used ClonMapper to identify two distinct, therapeutically-relevant cell populations within a CLL cell line and to gain insights into how clones' accumulated mutations fuel unique transcriptional profiles. 

To be precise

To overcome limitations of conventional imaging tests or endogenous biomarkers for cancer diagnosis, Liangliang Hao (Koch Institute), institute member Sangeeta Bhatia of the Cancer Program, and colleagues developed a multimodal nanosensor for precision diagnostics. Their system delivers synthetic biomarkers that, through acidosis, are targeted to tumors and activated by the tumor microenvironment to shed reporters into biofluids. The biomarkers can also carry imaging probes for localizing primary and metastatic cancers, which the team demonstrated in mouse models of colorectal cancer. Described in Nature Materials, the platform could help track cancer non-invasively and possibly guide treatment decisions for multiple tumor types.

Joint risk for joint diseases

Some GWAS loci are associated with multiple diseases, but scientists don’t know if disease risk at each locus results from multiple independent mutations or a single pleiotropic variant. Now, Pushpanathan Muthuirulan (Harvard), Dewei Zhao (Dalian University), associate member Terence Capellini in the Medical and Population Genetics Program, and colleagues address this question for GDF5, a gene with known roles in joint formation. They report that two regulatory variants in GDF5 separately cause hip dysplasia and knee osteoarthritis, suggesting that variant specificity, not pleiotropy, leads to disease risk. Using ATAC-seq, the team found that in genes with multiple musculoskeletal disease associations, three-quarters displayed the same pattern. Read more in Nature Communications and a Harvard news story.

The roots of a sticky situation

Velcrins are a class of small molecules that selectively kill cancer cells by inducing complex formation between two cellular proteins, PDE3A and SLFN12. Together with colleagues in the Center for the Development of Therapeutics, the Cancer Program, and the Genetic Perturbation and Proteomics platforms, Colin Garvie, Xiaoyun Wu, Malvina Papanastasiou, Sooncheol Lee, associate director Chris Lemke, institute member Matthew Meyerson, and senior group leader and director Heidi Greulich took a series of biophysical, genetic, and biochemical approaches to understanding how the PDE3A-SLFN12 complex forms and how it causes cell death. They also found that SLFN12 is an RNase, and that its activity is required for velcrin response. This new mechanistic understanding will facilitate therapeutic development of velcrins, now in clinical trials. Read more in Nature Communications.

Mapping tumor responses to natural killer cells

Natural killer (NK) cells, a key component of the immune system, can potentially be transplanted from healthy donors into patients with cancer to fight their tumors. The lab of associate member Constantine Mitsiades in the Cancer Program (with Michal Sheffer as leading author) and colleagues from Dana-Farber, Broad, and other institutions systematically examined which molecular features in tumor cells determine their degree of sensitivity to these NK cells, using PRISM phenotypic screens and CRISPR gene-editing studies. Their results provide insights into interactions between NK and tumor cells, and may inform efforts to develop NK cell–based immunotherapies. Read the full story in Nature Genetics.

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