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Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR–Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers. A pediatric cancer dependency map generated with genome-scale CRISPR–Cas9 loss-of-function screens in 82 pediatric cancer cell lines highlights genetic dependencies across a range of tumor types.

Achieving precision oncology requires accurate identification of targetable cancer vulnerabilities in patients. Generally, genomic features are regarded as the state-of-the-art method for stratifying patients for targeted therapies. In this work, we conduct the first rigorous comparison of DNA- and expression-based predictive models for viability across five datasets encompassing chemical and genetic perturbations. We find that expression consistently outperforms DNA for predicting vulnerabilities, including many currently stratified by canonical DNA markers. Contrary to their perception in the literature, the most accurate expression-based models depend on few features and are amenable to biological interpretation. This work points to the importance of exploring more comprehensive expression profiling in clinical settings.

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate or the expression of a marker gene. Information-rich assays, such as gene-expression profiling, are generally not amenable to efficient profiling of a given perturbation across multiple cellular contexts. Here, we developed MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines, and combine it with Cell Hashing to further multiplex additional experimental conditions, such as multiple post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and can be used to predict long-term cell viability from short-term transcriptional responses to treatment.

Transactions of the Cumberland & Westmorland Antiquarian & Archaeological Society, 10, 35-54, Presents a summary of the history of mining in the Caldbeck fells, and describes the results of recent research carried out by local enthusiasts. Their findings have not only been pivotal in extending the known date for mining and smelting to before AD 1200, but have also provided the earliest known evidence for the use of tracked transport in the UK and possibly elsewhere. A major conclusion is that the historical research and practical work, including the discovery of a hitherto unknown level, has determined that the principal seat of Elizabethan mining at Caldbeck was the Silver Gill workings. Au/LD

Transactions of the Cumberland & Westmorland Antiquarian & Archaeological Society, 1, 89-104, Investigates the first well-documented large-scale copper mining and smelting operation in the UK -- active between 1566/68 and 1695. Its location had been forgotten but historical survey plus fieldwork including that by the Mines of Lakeland Exploration Society (MOLES) reveals Silver Gill as the likely locale.