Shimada K, Muchlich JL, Mitchison TJ.
A tool for browsing the Cancer Dependency Map reveals functional connections between genes and helps predict the efficacy and selectivity of candidate cancer drugs. bioRxiv. 2019.
Publisher's VersionAbstractIndividual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover gene dependency in hundreds of cancer cell lines. DepMap is a powerful drug discovery tool, but can be challenging to use without professional bioinformatics assistance. We combined CRISPR and shRNA screening data from DepMap and built a non-programmer-friendly browser (
https://labsyspharm.shinyapps.io/depmap) that reports, for each gene, the growth reduction that can be expected on the loss of a gene or inhibition of its action (efficacy) and the selectivity of this effect across cell lines. Cluster analysis revealed proteins that work together in pathways or complexes. This tool can be used to 1) predict the efficacy and selectivity of candidate drugs; 2) identify targets for highly selective drugs; 3) identify maximally sensitive cell lines for testing a drug; 4) target hop, i.e., navigate from an undruggable protein with the desired selectively profile, such as an activated oncogene, to more druggable targets with a similar profile; and 5) identify novel pathways needed for cancer cell growth and survival.
Nakanishi M, Mitchell RR, Benoit YD, Orlando L, Reid JC, Shimada K, Davidson KC, Shapovalova Z, Collins TJ, Nagy A, et al. Human Pluripotency Is Initiated and Preserved by a Unique Subset of Founder Cells. Cell. 2019;177 (4) :910-924.e22.
AbstractThe assembly of organized colonies is the earliest manifestation in the derivation or induction of pluripotency in vitro. However, the necessity and origin of this assemblance is unknown. Here, we identify human pluripotent founder cells (hPFCs) that initiate, as well as preserve and establish, pluripotent stem cell (PSC) cultures. PFCs are marked by N-cadherin expression (NCAD) and reside exclusively at the colony boundary of primate PSCs. As demonstrated by functional analysis, hPFCs harbor the clonogenic capacity of PSC cultures and emerge prior to commitment events or phenotypes associated with pluripotent reprogramming. Comparative single-cell analysis with pre- and post-implantation primate embryos revealed hPFCs share hallmark properties with primitive endoderm (PrE) and can be regulated by non-canonical Wnt signaling. Uniquely informed by primate embryo organization in vivo, our study defines a subset of founder cells critical to the establishment pluripotent state.
Shimada K, Mitchison TJ.
Unsupervised identification of disease states from high-dimensional physiological and histopathological profiles. Mol Syst Biol. 2019;15 (2) :e8636.
AbstractThe liver and kidney in mammals play central roles in protecting the organism from xenobiotics and are at high risk of xenobiotic-induced injury. Xenobiotic-induced tissue injury has been extensively studied from both classical histopathological and biochemical perspectives. Here, we introduce a machine-learning approach to analyze toxicological response. Unsupervised characterization of physiological and histological changes in a large toxicogenomic dataset revealed nine discrete toxin-induced disease states, some of which correspond to known pathology, but others were novel. Analysis of dynamics revealed transitions between disease states at constant toxin exposure, mostly toward decreased pathology, implying induction of tolerance. Tolerance correlated with induction of known xenobiotic defense genes and decrease of novel ferroptosis sensitivity biomarkers, suggesting ferroptosis as a druggable driver of tissue pathophysiology. Lastly, mechanism of body weight decrease, a known primary marker for xenobiotic toxicity, was investigated. Combined analysis of food consumption, body weight, and molecular biomarkers indicated that organ injury promotes cachexia by whole-body signaling through Gdf15 and Igf1, suggesting strategies for therapeutic intervention that may be broadly relevant to human disease.