Cell. 2022 May 12:S0092-8674(22)00460-3. doi: 10.1016/j.cell.2022.04.013. Online ahead of print.

ABSTRACT

The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.

PMID:35580586 | DOI:10.1016/j.cell.2022.04.013

Cell. 2022 May 11:S0092-8674(22)00526-8. doi: 10.1016/j.cell.2022.04.028. Online ahead of print.

ABSTRACT

Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade IFN responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks IFN signaling independently of cell death inhibitory activity. Rather, IFN inhibition was mediated by the binding of OspC1 and OspC3 to the Ca²⁺ sensor calmodulin (CaM), blocking CaM kinase II and downstream JAK/STAT signaling. The growth of Shigella lacking OspC1 and OspC3 was attenuated in epithelial cells and in a murine model of infection. This phenotype was rescued in both models by the depletion of IFN receptors. OspC homologs conserved in additional pathogens not only bound CaM but also inhibited IFN, suggesting a widespread virulence strategy. These findings reveal a conserved but previously undescribed molecular mechanism of IFN inhibition and demonstrate the critical role of Ca²⁺ and IFN targeting in bacterial pathogenesis.

PMID:35568036 | DOI:10.1016/j.cell.2022.04.028

Cell. 2022 May 2:S0092-8674(22)00533-5. doi: 10.1016/j.cell.2022.04.035. Online ahead of print.

ABSTRACT

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1.

PMID:35568035 | PMC:PMC9057982 | DOI:10.1016/j.cell.2022.04.035

Cell. 2022 Apr 27:S0092-8674(22)00527-X. doi: 10.1016/j.cell.2022.04.029. Online ahead of print.

ABSTRACT

Breakthrough infections by SARS-CoV-2 variants become the global challenge for pandemic control. Previously, we developed the protein subunit vaccine ZF2001 based on the dimeric receptor-binding domain (RBD) of prototype SARS-CoV-2. Here, we developed a chimeric RBD-dimer vaccine approach to adapt SARS-CoV-2 variants. A prototype-Beta chimeric RBD-dimer was first designed to adapt the resistant Beta variant. Compared with its homotypic forms, the chimeric vaccine elicited broader sera neutralization of variants and conferred better protection in mice. The protection of the chimeric vaccine was further verified in macaques. This approach was generalized to develop Delta-Omicron chimeric RBD-dimer to adapt the currently prevalent variants. Again, the chimeric vaccine elicited broader sera neutralization of SARS-CoV-2 variants and conferred better protection against challenge by either Delta or Omicron SARS-CoV-2 in mice. The chimeric approach is applicable for rapid updating of immunogens, and our data supported the use of variant-adapted multivalent vaccine against circulating and emerging variants.

PMID:35568034 | PMC:PMC9042943 | DOI:10.1016/j.cell.2022.04.029

Cell. 2022 May 10:S0092-8674(22)00471-8. doi: 10.1016/j.cell.2022.04.024. Online ahead of print.

ABSTRACT

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

PMID:35568033 | DOI:10.1016/j.cell.2022.04.024

Cell. 2022 May 9:S0092-8674(22)00455-X. doi: 10.1016/j.cell.2022.04.008. Online ahead of print.

ABSTRACT

The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.

PMID:35561686 | DOI:10.1016/j.cell.2022.04.008

Cell. 2022 May 11:S0092-8674(22)00469-X. doi: 10.1016/j.cell.2022.04.022. Online ahead of print.

ABSTRACT

Across biological scales, gene-regulatory networks employ autorepression (negative feedback) to maintain homeostasis and minimize failure from aberrant expression. Here, we present a proof of concept that disrupting transcriptional negative feedback dysregulates viral gene expression to therapeutically inhibit replication and confers a high evolutionary barrier to resistance. We find that nucleic-acid decoys mimicking cis-regulatory sites act as "feedback disruptors," break homeostasis, and increase viral transcription factors to cytotoxic levels (termed "open-loop lethality"). Feedback disruptors against herpesviruses reduced viral replication >2-logs without activating innate immunity, showed sub-nM IC₅₀, synergized with standard-of-care antivirals, and inhibited virus replication in mice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptor escape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putative feedback circuit also generated open-loop lethality, reducing viral titers by >1-log. These results demonstrate that generating open-loop lethality, via negative-feedback disruption, may yield a class of antimicrobials with a high genetic barrier to resistance.

PMID:35561685 | PMC:PMC9097017 | DOI:10.1016/j.cell.2022.04.022

Cell. 2022 May 9:S0092-8674(22)00472-X. doi: 10.1016/j.cell.2022.04.025. Online ahead of print.

ABSTRACT

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.

PMID:35561684 | DOI:10.1016/j.cell.2022.04.025

Cell. 2022 May 12;185(10):1627-1629. doi: 10.1016/j.cell.2022.04.027.

ABSTRACT

Dendrites endow neurons with multiple compartments within their elaborate morphologies. In a recent study published in the journal Science, O'Hare et al. (2022) used elegant techniques to show that augmenting the intracellular calcium released by the endoplasmic reticulum caused behaviorally relevant plasticity to occur in spatially distinct dendritic compartments.

PMID:35561664 | DOI:10.1016/j.cell.2022.04.027

Cell. 2022 May 12;185(10):1625-1627. doi: 10.1016/j.cell.2022.04.026.

ABSTRACT

The generation of spatial transcriptomes of whole embryo has been limited in scale and resolution due to various technological restrictions. In this issue of Cell, Chen et al. introduce a DNA nanoball-based sample-capture technology for spatial transcriptome analysis to generate a molecular atlas of mouse organogenesis at single-cell resolution.

PMID:35561663 | DOI:10.1016/j.cell.2022.04.026

Cell. 2022 May 12;185(10):1623-1625. doi: 10.1016/j.cell.2022.04.018.

ABSTRACT

In this issue of Cell, Wei et al. show that the increased cardiovascular risks associated with cannabis use are mediated by proinflammatory cannabinoid 1 (CB1) receptor signaling, which can be ameliorated with the natural antioxidant agent genistein.

PMID:35561662 | DOI:10.1016/j.cell.2022.04.018

Cell. 2022 May 12;185(10):1619-1622. doi: 10.1016/j.cell.2022.04.012.

ABSTRACT

Progress in studying sex as a biological variable (SABV) is slow, and the influence of gendered effects of the social environment on biology is largely unknown. Yet incorporating these concepts into basic science research will enhance our understanding of human health and disease. We provide steps to move this process forward.

PMID:35561661 | DOI:10.1016/j.cell.2022.04.012

Cell. 2022 May 6:S0092-8674(22)00470-6. doi: 10.1016/j.cell.2022.04.023. Online ahead of print.

ABSTRACT

During vertebrate embryogenesis, cell collectives engage in coordinated behavior to form tissue structures of increasing complexity. In the avian skin, assembly into follicles depends on intrinsic mechanical forces of the dermis, but how cell mechanics initiate pattern formation is not known. Here, we reconstitute the initiation of follicle patterning ex vivo using only freshly dissociated avian dermal cells and collagen. We find that contractile cells physically rearrange the extracellular matrix (ECM) and that ECM rearrangement further aligns cells. This exchange transforms a mechanically unlinked collective of dermal cells into a continuum, with coherent, long-range order. Combining theory with experiment, we show that this ordered cell-ECM layer behaves as an active contractile fluid that spontaneously forms regular patterns. Our study illustrates a role for mesenchymal dynamics in generating cell-level ordering and tissue-level patterning through a fluid instability-processes that may be at play across morphological symmetry-breaking contexts.

PMID:35551765 | DOI:10.1016/j.cell.2022.04.023

Cell. 2022 May 5:S0092-8674(22)00467-6. doi: 10.1016/j.cell.2022.04.020. Online ahead of print.

ABSTRACT

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

PMID:35545089 | DOI:10.1016/j.cell.2022.04.020

Cell. 2022 May 1:S0092-8674(22)00466-4. doi: 10.1016/j.cell.2022.04.019. Online ahead of print.

ABSTRACT

For many solid malignancies, lymph node (LN) involvement represents a harbinger of distant metastatic disease and, therefore, an important prognostic factor. Beyond its utility as a biomarker, whether and how LN metastasis plays an active role in shaping distant metastasis remains an open question. Here, we develop a syngeneic melanoma mouse model of LN metastasis to investigate how tumors spread to LNs and whether LN colonization influences metastasis to distant tissues. We show that an epigenetically instilled tumor-intrinsic interferon response program confers enhanced LN metastatic potential by enabling the evasion of NK cells and promoting LN colonization. LN metastases resist T cell-mediated cytotoxicity, induce antigen-specific regulatory T cells, and generate tumor-specific immune tolerance that subsequently facilitates distant tumor colonization. These effects extend to human cancers and other murine cancer models, implicating a conserved systemic mechanism by which malignancies spread to distant organs.

PMID:35525247 | DOI:10.1016/j.cell.2022.04.019

Cell. 2022 May 2:S0092-8674(22)00464-0. doi: 10.1016/j.cell.2022.04.017. Online ahead of print.

ABSTRACT

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1 retrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or retrotransposons. Since flanking repeats promote non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7 × 10^-4 per locus per generation. Recurrent inversions exhibit a sex-chromosomal bias and co-localize with genomic disorder critical regions. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes specific haplotypes to disease-causing CNVs.

PMID:35525246 | DOI:10.1016/j.cell.2022.04.017

Cell. 2022 Apr 28:S0092-8674(22)00462-7. doi: 10.1016/j.cell.2022.04.015. Online ahead of print.

ABSTRACT

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.

PMID:35523183 | DOI:10.1016/j.cell.2022.04.015

Cell. 2022 Apr 8:S0092-8674(22)00456-1. doi: 10.1016/j.cell.2022.04.009. Online ahead of print.

ABSTRACT

We examined antibody and memory B cell responses longitudinally for ∼9-10 months after primary 2-dose SARS-CoV-2 mRNA vaccination and 3 months after a 3rd dose. Antibody decay stabilized between 6 and 9 months, and antibody quality continued to improve for at least 9 months after 2-dose vaccination. Spike- and RBD-specific memory B cells remained durable over time, and 40%-50% of RBD-specific memory B cells simultaneously bound the Alpha, Beta, Delta, and Omicron variants. Omicron-binding memory B cells were efficiently reactivated by a 3rd dose of wild-type vaccine and correlated with the corresponding increase in neutralizing antibody titers. In contrast, pre-3rd dose antibody titers inversely correlated with the fold-change of antibody boosting, suggesting that high levels of circulating antibodies may limit the added protection afforded by repeat short interval boosting. These data provide insight into the quantity and quality of mRNA-vaccine-induced immunity over time through 3 or more antigen exposures.

PMID:35523182 | PMC:PMC8989683 | DOI:10.1016/j.cell.2022.04.009

Cell. 2022 May 12;185(10):1777-1792.e21. doi: 10.1016/j.cell.2022.04.003. Epub 2022 May 4.

ABSTRACT

Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.

PMID:35512705 | DOI:10.1016/j.cell.2022.04.003

Cell. 2022 Apr 27:S0092-8674(22)00461-5. doi: 10.1016/j.cell.2022.04.014. Online ahead of print.

ABSTRACT

Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAF^V600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.

PMID:35512704 | DOI:10.1016/j.cell.2022.04.014

Cell. 2022 May 12;185(10):1630-1645. doi: 10.1016/j.cell.2022.04.004. Epub 2022 May 2.

ABSTRACT

Atherosclerosis is an inflammatory disease of the large arteries that is the major cause of cardiovascular disease (CVD) and stroke. Here, we review the current understanding of the molecular, cellular, genetic, and environmental contributions to atherosclerosis, from both individual pathway and systems perspectives. We place an emphasis on recent developments, some of which have yielded unexpected biology, including previously unknown heterogeneity of inflammatory and smooth muscle cells in atherosclerotic lesions, roles for senescence and clonal hematopoiesis, and links to the gut microbiome.

PMID:35504280 | DOI:10.1016/j.cell.2022.04.004

Cell. 2022 May 12;185(10):1676-1693.e23. doi: 10.1016/j.cell.2022.04.005. Epub 2022 Apr 29.

ABSTRACT

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ⁹-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ⁹-THC. In mice, genistein blocked Δ⁹-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ⁹-THC-induced atherosclerosis.

PMID:35489334 | DOI:10.1016/j.cell.2022.04.005

Cell. 2022 Apr 28;185(9):1618-1618.e1. doi: 10.1016/j.cell.2022.03.028.

ABSTRACT

Skeletal muscle size is highly plastic and sensitive to a variety of stimuli. Muscle atrophy occurs as the result of changes in multiple signaling pathways that regulate both protein synthesis and degradation. The signaling pathways that are activated or inhibited depend on the specific stimuli that are altered. To view this SnapShot, open of download the PDF.

PMID:35487192 | DOI:10.1016/j.cell.2022.03.028

Cell. 2022 Apr 28;185(9):1602-1617.e17. doi: 10.1016/j.cell.2022.04.001.

ABSTRACT

Prefrontal cortex (PFC) is postulated to exert "top-down control" on information processing throughout the brain to promote specific behaviors. However, pathways mediating top-down control remain poorly understood. In particular, knowledge about direct prefrontal connections that might facilitate top-down control of hippocampal information processing remains sparse. Here we describe monosynaptic long-range GABAergic projections from PFC to hippocampus. These preferentially inhibit vasoactive intestinal polypeptide-expressing interneurons, which are known to disinhibit hippocampal microcircuits. Indeed, stimulating prefrontal-hippocampal GABAergic projections increases hippocampal feedforward inhibition and reduces hippocampal activity in vivo. The net effect of these actions is to specifically enhance the signal-to-noise ratio for hippocampal encoding of object locations and augment object-induced increases in spatial information. Correspondingly, activating or inhibiting these projections promotes or suppresses object exploration, respectively. Together, these results elucidate a top-down prefrontal pathway in which long-range GABAergic projections target disinhibitory microcircuits, thereby enhancing signals and network dynamics underlying exploratory behavior.

PMID:35487191 | DOI:10.1016/j.cell.2022.04.001

Cell. 2022 Apr 28;185(9):1455-1470. doi: 10.1016/j.cell.2022.04.002.

ABSTRACT

Diet as a whole, encompassing food composition, calorie intake, and the length and frequency of fasting periods, affects the time span in which health and functional capacity are maintained. Here, we analyze aging and nutrition studies in simple organisms, rodents, monkeys, and humans to link longevity to conserved growth and metabolic pathways and outline their role in aging and age-related disease. We focus on feasible nutritional strategies shown to delay aging and/or prevent diseases through epidemiological, model organism, clinical, and centenarian studies and underline the need to avoid malnourishment and frailty. These findings are integrated to define a longevity diet based on a multi-pillar approach adjusted for age and health status to optimize lifespan and healthspan in humans.

PMID:35487190 | PMC:PMC9089818 | DOI:10.1016/j.cell.2022.04.002

Cell. 2022 Apr 28;185(9):1451-1454. doi: 10.1016/j.cell.2022.04.006.

ABSTRACT

Natural killer (NK)-based therapies against cancer are emerging, but the understanding of NK cell functions needs to be completed to optimize these treatments. In this issue, Pan et al. (2022) show that pro-apoptotic molecules, such as BH3-mimetics, synergize with NK cells to induce mitochondria-driven apoptosis in tumor cells, thereby enhancing the efficacy of NK cell therapies.

PMID:35487189 | DOI:10.1016/j.cell.2022.04.006

Cell. 2022 Apr 28;185(9):1449-1451. doi: 10.1016/j.cell.2022.04.007.

ABSTRACT

Microbial specialized metabolites play key roles in microbiome interactions, but their biosynthetic pathways are difficult to characterize. In this issue, Patel et al. (2022) describe new technologies for the computer-aided redesign of gene clusters to facilitate heterologous expression across diverse hosts and showcase their utility by identifying a new class of microbiome-derived nucleotide metabolites.

PMID:35487188 | DOI:10.1016/j.cell.2022.04.007

Cell. 2022 Apr 28;185(9):1445-1448. doi: 10.1016/j.cell.2022.03.046.

ABSTRACT

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.

PMID:35487187 | DOI:10.1016/j.cell.2022.03.046

Cell. 2022 May 12;185(10):1745-1763.e22. doi: 10.1016/j.cell.2022.03.041. Epub 2022 Apr 27.

ABSTRACT

Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.

PMID:35483375 | DOI:10.1016/j.cell.2022.03.041

Cell. 2022 May 12;185(10):1709-1727.e18. doi: 10.1016/j.cell.2022.03.043. Epub 2022 Apr 27.

ABSTRACT

Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.

PMID:35483374 | PMC:PMC9106933 | DOI:10.1016/j.cell.2022.03.043

Cell. 2022 May 12;185(10):1661-1675.e16. doi: 10.1016/j.cell.2022.03.042. Epub 2022 Apr 27.

ABSTRACT

β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in its basal state. Its engagement with a phosphopeptide mimicking phosphorylated receptor tail efficiently releases the β-arrestin tail from its N domain to assume distinct conformations. Unexpectedly, we find that β-arrestin binding to phosphorylated receptor, with a phosphorylation barcode identical to the isolated phosphopeptide, is highly inefficient and that agonist-promoted receptor activation is required for β-arrestin activation, consistent with the release of a sequestered receptor C tail. These findings, together with focused cellular investigations, reveal that agonism and receptor C-tail release are specific determinants of the rate and efficiency of β-arrestin activation by phosphorylated receptor. We infer that receptor phosphorylation patterns, in combination with receptor agonism, synergistically establish the strength and specificity with which diverse, downstream β-arrestin-mediated events are directed.

PMID:35483373 | DOI:10.1016/j.cell.2022.03.042

Cell. 2022 May 12;185(10):1793-1805.e17. doi: 10.1016/j.cell.2022.03.040. Epub 2022 Apr 27.

ABSTRACT

The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose-dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue.

PMID:35483372 | PMC:PMC9106931 | DOI:10.1016/j.cell.2022.03.040

Cell. 2022 May 12;185(10):1764-1776.e12. doi: 10.1016/j.cell.2022.03.039. Epub 2022 Apr 25.

ABSTRACT

Mitochondrial DNA (mtDNA) editing paves the way for disease modeling of mitochondrial genetic disorders in cell lines and animals and also for the treatment of these diseases in the future. Bacterial cytidine deaminase DddA-derived cytosine base editors (DdCBEs) enabling mtDNA editing, however, are largely limited to C-to-T conversions in the 5'-TC context (e.g., TC-to-TT conversions), suitable for generating merely 1/8 of all possible transition (purine-to-purine and pyrimidine-to-pyrimidine) mutations. Here, we present transcription-activator-like effector (TALE)-linked deaminases (TALEDs), composed of custom-designed TALE DNA-binding arrays, a catalytically impaired, full-length DddA variant or split DddA originated from Burkholderia cenocepacia, and an engineered deoxyadenosine deaminase derived from the E. coli TadA protein, which induce targeted A-to-G editing in human mitochondria. Custom-designed TALEDs were highly efficient in human cells, catalyzing A-to-G conversions at a total of 17 target sites in various mitochondrial genes with editing frequencies of up to 49%.

PMID:35472302 | DOI:10.1016/j.cell.2022.03.039

Cell. 2022 May 12;185(10):1728-1744.e16. doi: 10.1016/j.cell.2022.03.044. Epub 2022 Apr 1.

ABSTRACT

As the emerging variants of SARS-CoV-2 continue to drive the worldwide pandemic, there is a constant demand for vaccines that offer more effective and broad-spectrum protection. Here, we report a circular RNA (circRNA) vaccine that elicited potent neutralizing antibodies and T cell responses by expressing the trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in both mice and rhesus macaques. Notably, the circRNA vaccine enabled higher and more durable antigen production than the 1mΨ-modified mRNA vaccine and elicited a higher proportion of neutralizing antibodies and distinct Th1-skewed immune responses. Importantly, we found that the circRNA^RBD-Omicron vaccine induced effective neutralizing antibodies against the Omicron but not the Delta variant. In contrast, the circRNA^RBD-Delta vaccine protected against both Delta and Omicron or functioned as a booster after two doses of either native- or Delta-specific vaccination, making it a favorable choice against the current variants of concern (VOCs) of SARS-CoV-2.

PMID:35460644 | PMC:PMC8971115 | DOI:10.1016/j.cell.2022.03.044

Cell. 2022 Apr 28;185(9):1572-1587.e11. doi: 10.1016/j.cell.2022.03.037. Epub 2022 Mar 28.

ABSTRACT

The large number of spike substitutions in Omicron lineage variants (BA.1, BA.1.1., and BA.2) could jeopardize the efficacy of SARS-CoV-2 vaccines. We evaluated in mice the protective efficacy of the Moderna mRNA-1273 vaccine against BA.1 before or after boosting. Whereas two doses of mRNA-1273 vaccine induced high levels of neutralizing antibodies against historical WA1/2020 strains, lower levels against BA.1 were associated with breakthrough infection and inflammation in the lungs. A primary vaccination series with mRNA-1273.529, an Omicron-matched vaccine, potently neutralized BA.1 but inhibited historical or other SARS-CoV-2 variants less effectively. However, boosting with either mRNA-1273 or mRNA-1273.529 vaccines increased neutralizing titers and protection against BA.1 and BA.2 infection. Nonetheless, the neutralizing antibody titers were higher, and lung viral burden and cytokines were slightly lower in mice boosted with mRNA-1273.529 and challenged with BA.1. Thus, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against Omicron infection with limited differences in efficacy measured.

PMID:35452622 | PMC:PMC8958157 | DOI:10.1016/j.cell.2022.03.037

Cell. 2022 May 12;185(10):1694-1708.e19. doi: 10.1016/j.cell.2022.03.033. Epub 2022 Apr 20.

ABSTRACT

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.

PMID:35447074 | DOI:10.1016/j.cell.2022.03.033

Cell. 2022 May 12;185(10):1646-1660.e18. doi: 10.1016/j.cell.2022.03.034. Epub 2022 Apr 20.

ABSTRACT

Incomplete lineage sorting (ILS) makes ancestral genetic polymorphisms persist during rapid speciation events, inducing incongruences between gene trees and species trees. ILS has complicated phylogenetic inference in many lineages, including hominids. However, we lack empirical evidence that ILS leads to incongruent phenotypic variation. Here, we performed phylogenomic analyses to show that the South American monito del monte is the sister lineage of all Australian marsupials, although over 31% of its genome is closer to the Diprotodontia than to other Australian groups due to ILS during ancient radiation. Pervasive conflicting phylogenetic signals across the whole genome are consistent with some of the morphological variation among extant marsupials. We detected hundreds of genes that experienced stochastic fixation during ILS, encoding the same amino acids in non-sister species. Using functional experiments, we confirm how ILS may have directly contributed to hemiplasy in morphological traits that were established during rapid marsupial speciation ca. 60 mya.

PMID:35447073 | DOI:10.1016/j.cell.2022.03.034

Cell. 2022 Apr 28;185(9):1556-1571.e18. doi: 10.1016/j.cell.2022.03.038. Epub 2022 Mar 25.

ABSTRACT

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID₅₀ at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

PMID:35447072 | PMC:PMC8947944 | DOI:10.1016/j.cell.2022.03.038

Cell. 2022 Apr 28;185(9):1521-1538.e18. doi: 10.1016/j.cell.2022.03.030. Epub 2022 Apr 20.

ABSTRACT

Interest in harnessing natural killer (NK) cells for cancer immunotherapy is rapidly growing. However, efficacy of NK cell-based immunotherapy remains limited in most trials. Strategies to augment the killing efficacy of NK cells are thus much needed. In the current study, we found that mitochondrial apoptosis (mtApoptosis) pathway is essential for efficient NK killing, especially at physiologically relevant effector-to-target ratios. Furthermore, NK cells can prime cancer cells for mtApoptosis and mitochondrial priming status affects cancer-cell susceptibility to NK-mediated killing. Interestingly, pre-activating NK cells confers on them resistance to BH3 mimetics. Combining BH3 mimetics with NK cells synergistically kills cancer cells in vitro and suppresses tumor growth in vivo. The ideal BH3 mimetic to use in such an approach can be predicted by BH3 profiling. We herein report a rational and precision strategy to augment NK-based immunotherapy, which may be adaptable to T cell-based immunotherapies as well.

PMID:35447071 | PMC:PMC9097966 | DOI:10.1016/j.cell.2022.03.030

Cell. 2022 Apr 28;185(9):1539-1548.e5. doi: 10.1016/j.cell.2022.03.019. Epub 2022 Mar 18.

ABSTRACT

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

PMID:35429436 | PMC:PMC8930394 | DOI:10.1016/j.cell.2022.03.019

Cell. 2022 Apr 14;185(8):1444-1444.e1. doi: 10.1016/j.cell.2022.03.027.

ABSTRACT

The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.

PMID:35427500 | DOI:10.1016/j.cell.2022.03.027

Cell. 2022 Apr 14;185(8):1431-1443.e16. doi: 10.1016/j.cell.2022.03.023.

ABSTRACT

Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.

PMID:35427499 | PMC:PMC9108009 | DOI:10.1016/j.cell.2022.03.023

Cell. 2022 Apr 14;185(8):1294-1296. doi: 10.1016/j.cell.2022.03.035.

ABSTRACT

Can gut-residing bacteria influence mood and anxiety? And can targeting bacteria-produced metabolites reduce anxiety? Based on two Nature and Nature Medicine papers, the answers to these questions are likely yes. Needham, Campbell, and colleagues identified bacteria that enhance anxiety-like behaviors in mice and ways to mitigate anxiety in autistic patients.

PMID:35427498 | DOI:10.1016/j.cell.2022.03.035

Cell. 2022 Apr 14;185(8):1292-1294. doi: 10.1016/j.cell.2022.03.013.

ABSTRACT

Tumors contain bacteria, but the functional significance of this tumor microbiota is not appreciated. Fu et al. show that bacteria within breast tumor cells contribute to metastasis, in part, by enhancing tumor cell survival to mechanical fluid shear stress as would be found in the circulation.

PMID:35427497 | DOI:10.1016/j.cell.2022.03.013

Cell. 2022 Apr 14;185(8):1290-1292. doi: 10.1016/j.cell.2022.03.032.

ABSTRACT

Neurodegenerative diseases commonly exhibit aggregation of specific proteins that define each disease. Chang et al. (2022) establish that a C-terminal fragment of TMEM106B, a frontotemporal-lobar-degeneration risk factor, unexpectedly forms amyloid fibrils with similar structures in diverse neurodegenerative disorders. These unanticipated TMEM106B(120-254) fibrils may herald etiological shifts for several neurodegenerative diseases.

PMID:35427496 | DOI:10.1016/j.cell.2022.03.032

Cell. 2022 Apr 28;185(9):1549-1555.e11. doi: 10.1016/j.cell.2022.03.024. Epub 2022 Mar 17.

ABSTRACT

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.

PMID:35427477 | PMC:PMC8926910 | DOI:10.1016/j.cell.2022.03.024

Cell. 2022 Apr 28;185(9):1588-1601.e14. doi: 10.1016/j.cell.2022.03.018. Epub 2022 Mar 17.

ABSTRACT

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4⁺ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4⁺ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.

PMID:35413241 | PMC:PMC8926873 | DOI:10.1016/j.cell.2022.03.018

Cell. 2022 Apr 14;185(8):1356-1372.e26. doi: 10.1016/j.cell.2022.02.027. Epub 2022 Apr 7.

ABSTRACT

Tumor-resident intracellular microbiota is an emerging tumor component that has been documented for a variety of cancer types with unclear biological functions. Here, we explored the functional significance of these intratumor bacteria, primarily using a murine spontaneous breast-tumor model MMTV-PyMT. We found that depletion of intratumor bacteria significantly reduced lung metastasis without affecting primary tumor growth. During metastatic colonization, intratumor bacteria carried by circulating tumor cells promoted host-cell survival by enhancing resistance to fluid shear stress by reorganizing actin cytoskeleton. We further showed that intratumor administration of selected bacteria strains isolated from tumor-resident microbiota promoted metastasis in two murine tumor models with significantly different levels of metastasis potential. Our findings suggest that tumor-resident microbiota, albeit at low biomass, play an important role in promoting cancer metastasis, intervention of which might therefore be worth exploring for advancing oncology care.

PMID:35395179 | DOI:10.1016/j.cell.2022.02.027

Cell. 2022 Apr 14;185(8):1283-1286. doi: 10.1016/j.cell.2022.03.036. Epub 2022 Apr 6.

ABSTRACT

The brutal attack on Ukraine by the Russian Federation has shocked the world. While the world works to end the violence and help refugees, as a scientific journal, our thoughts are also with those in the scientific community who are directly or indirectly impacted by the war. We have been inspired by and applaud the labs around the world that have opened their doors to displaced scientists and remain committed to supporting scientists, whoever and wherever they are. Because science requires collaboration and trust, we urge the scientific community to continue efforts like this and to remain united, especially in times as difficult as these. In this Voices piece, we feature short comments from scientists from Ukraine and scientists from Russia. This small sampling is far from exhaustive, but our sincere thanks go to those scientists who were willing to share their thoughts on this volatile and emotionally charged situation; the views expressed are those of the contributors alone. We join the world in hoping for a swift resolution to the conflict, for the good of humanity.

PMID:35390273 | DOI:10.1016/j.cell.2022.03.036

Cell. 2022 Apr 14;185(8):1275-1278. doi: 10.1016/j.cell.2022.03.029. Epub 2022 Apr 5.

ABSTRACT

Dr. Deborah J. Cook's contributions in the field of critical care have not only impacted the intensive care unit (ICU) patients she treats and countless others worldwide but have also helped establish research programs and clinical trials as integral components of improving care and outcomes for the most seriously ill. Lara Szewczak spoke with Dr. Cook, recipient of the 2022 Canada Gairdner Wightman award, about critical care research, her reflections on the COVID-19 pandemic, and her views on mentorship. An edited version of this conversation is presented below.

PMID:35385690 | PMC:PMC8979764 | DOI:10.1016/j.cell.2022.03.029