Cancer cells can rewire genetic and epigenetic regulatory networks to promote cell proliferation and evade the immune system. Using a focused CRISPR/Cas9 genetic screen, Cuellar et al. identify a novel role for the SETDB1 histone methyltransferase in regulating the antiviral response in AML cells via the suppression of transposable elements.

SUMMARY Animal development is characterized by signaling events that occur at precise locations and times within the embryo, yet determining when and where such precision is needed for proper embryogenesis has been a longstanding challenge. Here we address this question for Erk signaling, a key developmental patterning cue. We describe an optogenetic system for activating Erk with high spatiotemporal precision in vivo. Implementing this system in Drosophila, we find that embryogenesis is remarkably robust to ectopic Erk signaling, except from 1 to 4 hours post fertilization when perturbing the spatial extent of Erk pathway activation leads to dramatic disruptions of patterning and morphogenesis. Later in development, the effects of ectopic signaling are buffered, at least in part by combinatorial mechanisms. Our approach can be used to systematically probe the differential contributions of the Erk pathway and concurrent signals, leading to a more quantitative understanding of developmental signaling.

Even amongst genetically identical cancer cells, therapy resistance often only emerges from a very small subset of those cells. Much effort has gone into uncovering the molecular differences in rare individual cells in the initial population that may allow certain cells to become therapy resistant; however, comparatively little is known about variability in the resistant outcomes themselves. Here, we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically, and functionally distinct fate types. These different resistant types are largely predetermined by molecular differences between cells before addition of drug and not by extrinsic cell-specific microenvironmental factors. Changes in dose and kind of drug can, however, switch the resistant fate type of an initial cell, even resulting in the generation and elimination of certain fate types. Diversity in resistant fates was observed across several single-cell-derived cancer cell lines and types treated with a variety of drugs. Cell fate diversity as a result of variability in intrinsic cell states may be a generic feature of response to external cues.

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Highlights d Rare coordinated high expression states in cancer cells can drive therapy resistance d Gene networks with transcriptional bursting recapitulate these transcriptional states d Networks with low connectivity favorably give rise to these states d Parameters affecting transcriptional bursting are critical to produce these states

RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment.