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The Mouse Cancer Cell line Atlas (MCCA) provides major advances towards a mechanistic understanding of cancer genomes.

Krapić, Kavazović and colleagues dissect the mechanism by which natural killer cells drive adipose tissue remodelling during viral infection, thus fuelling antiviral immune responses.

The immune system is tolerized against the neuromyelitis optica autoantigen AQP4 by thymic B cells, which present their endogenous AQP4 to AQP4-reactive thymocytes.

Immune cells are generally considered to be able to move through tissues using nonadhesive amoeboid migration mechanics. Here, the authors show that, unlike other immune cells, mast cells do not use this method and instead are completely reliant on integrin–ECM interactions.

Invariant natural killer T (NKT) cells are defined into subset based on transcription expression and cytokine production, but differences in the subset distributions of these cells are seen between inbred mouse strains. Here the authors show that CD1d mediated TCR signals along with intrinsic signals impact this strain specific difference in the composition of the NKT cell compartment.

Mutations in the RNA-binding protein roquin-1 are known to result in humoral autoimmunity. Heissmeyer and colleagues show that MALT1 cleavage of roquin and regnase-1 downstream of TCR signaling releases cooperatively repressed targets to promote T_H17 cell differentiation

The differentiation and function of regulatory T (Treg) cells are critically controlled by T cell receptor (TCR) signaling. Here the authors show that CARD11-BCL10-MALT1 (CBM) complexes are dispensable for effector Treg conversion under inflammatory conditions but are critical for mediating Treg suppressive activity in a MALT1 paracaspase-dependent manner.

How transcription factor NF-κB influences B cell development remains enigmatic. Rajewsky and colleagues show that NF-κB activation driven by the kinase IKK is required for the generation of B cells expressing immunoglobulin-λ but not immunoglobulin-κ light chains.

Klein and colleagues show that the lysosomal cysteine protease cathepsin L shapes the diversity and optimizes the fitness of clones that enter the CD4⁺ T cell repertoire.

Epithelial NF-κB preserves the integrity of the gut epithelial barrier and coordinates the antimicrobial actions of the innate and adaptive immune systems. Deficiency in or hyperactivation of this transcription factor results in chronic inflammatory bowel disease.

De la Rosa et al. developed an in vivo CRISPR screening system to dissect macrophage regulation in multiple sclerosis models, revealing key cytokine signaling pathways that control myeloid cell behavior in neuroinflammation.

Preclinical molecular models are useful that mimic a patient´s response to targeted therapy. Here, the authors establish an in vivo inducible RNAi-mediated gene silencing system in patient-derived xenograft models of acute leukemia to identify individual vulnerabilities and therapeutic targets.

A CasRx-based screening platform for genome-scale long noncoding RNA transcriptome perturbation is described.

Sustained exogenous Notch2 signaling prompts Follicular B cells to trans-differentiate into Marginal Zone B cells. This study reveals that under physiological conditions, Notch2 signalling regulates a fate choice in antigen activated Follicular B cells, dictating whether they develop into Germinal Center B cells or Marginal Zone B cells.

Notch signalling is central to marginal zone B cell development, but it is unclear what path this development takes in vivo. Here the authors use a mouse that lacks these cells to show that transgenic induction of Notch2 is sufficient for development of marginal zone B cells via transdifferentiation from follicular B cells and that this mechanism can occur in wildtype mice.

MALT1 regulates NFκB signalling both as a scaffolding protein and as a protease. Here the authors show that during T cell activation the expression of MALT1 gene switches to an alternatively spliced variant, which increases TCR signal transduction due to enhanced TRAF6 binding.

Saur and colleagues perform a high-throughput combinatorial drug screen and identify a synergistic combination between nintedanib and trametinib that sensitizes mesenchymal PDAC to immune checkpoint blockade.

Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.

The RNA-binding protein RC3H1/ROQUIN1 promotes the degradation of mRNA by binding to a consensus CDE present in the 3′UTR. Here the authors expand the set of consensus sequences through which RCH31 binds and regulates mRNA encoding members of the DNA damage response and IKK/NF-κB pathway.

B-cell maturation antigen (BCMA) regulates the survival of B cells and is essential for the maintenance of long-lived plasma cells. Here, the authors show that γ-secretase directly sheds BCMA from the cell surface and therefore regulates the number of plasma cells.

The Wnt pathway is one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL) and is activated in only a subset of patients; however, no universal drivers of the disease have been identified. Here the authors show that Notch2 and β-catenin pathways are the main drivers of the pro-survival bidirectional crosstalk between stromal cells and leukemic cells.

Korn and colleagues report that Sirpα⁺ dendritic cells trans-present the cytokine IL-6 to T cells through a process that requires its receptor IL-6Rα bound to dendritic cells and that trans-presentation is needed to generate pathogenic cells of the T_H17 subset of helper T cells in vivo.

Conditional gene targeting based on excision or inversion of loxP-flanked DNA segments by Cre recombinase is a powerful technology for the analysis of gene function, but unexpected expression patterns of cre transgenes, variability of recombination efficiency depending on the target gene and potential toxicity of Cre recombinase represent serious challenges for the experimenter.

In this Opinion article, Schneideret al. outline tissue- and cell type-specific differences in tumorigenesis and the organization of oncogenic signalling pathways, and discuss the implications of our understanding of tissue context on molecularly targeted therapy and clinical trial design.

Shigella infection can lead to stimulation of the NF-κB pathway. IpaH9.8, a Shigella effector with ubiquitin ligase activity polyubiquitylates NEMO, a key regulator of NF-κB activation, leading to its degradation and subsequent impairment of NF-κB activation.

Geert van Loo, Rudi Beyaert, Dirk Elewaut and colleagues report that myeloid-specific deletion of Tnfaip3 in mice causes spontaneous destructive polyarthritis that resembles rheumatoid arthritis. Tnfaip3 encodes the A20 protein, which is involved in negative regulation of NF-κB signaling in response to proinflammatory stimuli.

The authors provide protocols for rapid and scalable genome engineering in somatic cells of the liver and pancreas through both viral and nonviral delivery of CRISPR components into living mice.