Cell reports最新文献

Colorectal cancers (CRCs) display recurrent, non-random patterns of chromosome gains and losses, yet the functional contribution of these aneuploidies to colorectal tumorigenesis remains unclear. Mechanistic insights into the oncogenic driver potential of aneuploidy require improved experimental models that recapitulate CRC patient-relevant aneuploidy patterns. Developing such models demands a clear understanding of how aneuploidy evolves during the progression from pre-malignant adenoma to carcinoma and how aneuploidy patterns vary across CRC subtypes. In this review, we highlight and discuss context-dependent alterations in the aneuploidy landscape of CRC, examining associations with tumor subtype, tumor stage, whole-genome doubling, TP53 status, and metastatic organotropism. Through a synthesis of the current literature and meta-analysis of publicly available bulk sequencing datasets of colorectal carcinomas and colorectal adenomas, this review provides a comprehensive CRC aneuploidy framework to guide future studies aimed at unraveling the mechanistic and clinical implications of these copy-number alterations.

Janus kinases 1 and 2 and STAT transcription factors are critical signaling nodes for numerous growth factors. In the mammary gland, JAK2 and STAT5a/b are essential for alveolar cell differentiation and lactation, but little is known about the cooperative roles of JAKs and STATs before pregnancy. We examined female mice conditionally deficient in JAK1/2 and discovered that both kinases jointly regulate epithelial cell proliferation and ductal morphogenesis. To assess the role of downstream STATs, we generated genetic models co-deficient in STAT3/5a/5b with or without STAT1 or JAK1. Although loss of STAT3/5a/5b leads to a JAK1-dependent upregulation of STAT1, the formation of mammary ducts is unaffected by the lack of expression and activation of all seven STAT proteins. Additionally, STAT deficiency impairs the cytokine-induced autophosphorylation of JAK1/2. These findings suggest that mammary duct development is orchestrated by STAT-independent signaling mechanisms of JAK1 and JAK2, potentially beyond their roles as tyrosine kinases.

Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), few studies exist at the protein level. We perform a deep, multi-omics characterization (epigenome, transcriptome, and proteome) of HSCs in a mouse model carrying a loss-of-function mutation in Tet2, a driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile TET2-deficient (Tet2^-/-) HSCs, revealing previously unrecognized molecular processes that define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of wild-type and Tet2^-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as being dysregulated upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.

Myocytes are exceptionally long-lived cells that must maintain proteome integrity over decades while adjusting for changes in functional output and metabolic demand. We used in vivo stable isotope labeling combined with mass spectrometry proteomics and correlated multi-isotope imaging mass spectrometry to quantify and visualize protein turnover across cardiac, fast-twitch, and slow-twitch skeletal muscles, creating a resource of hundreds of individual protein turnover rates from each tissue. We found that cardiac muscle has the highest rate of protein turnover, followed by slow-twitch skeletal muscle and then fast-twitch skeletal muscle, and that these different rates of protein turnover are driven by different levels of muscle use, rather than myosin isoform composition. We also identified protein age heterogeneity at the myofiber and sarcomere levels. These findings uncover fundamental principles of muscle protein maintenance and have broad implications for understanding cellular aging, muscle disease, and the design of therapeutic strategies targeting muscle protein turnover.

Fibroblasts are abundant structural cells with an emerging immune-sentinel role in the wound healing process, though its functional significance remains incompletely explored. By utilizing an oral injury model that heals rapidly, we identify murine PI16⁺ reticular fibroblasts to be enriched in interleukin-33 (IL-33), an alarmin cytokine, and demonstrate that Il33 deletion in fibroblasts impairs oral wound healing. Single-cell RNA sequencing analysis points to regulatory T (Treg) cells, which respond to IL-33 by upregulating the expression of macrophage migration-inhibitory factor (MIF) and transforming growth factor β1 (TGF-β1). Mechanistically, MIF promotes monocyte recruitment, which facilitates angiogenesis, whereas TGF-β1 is linked to early macrophage transition to a pro-resolving phenotype. Importantly, human oral mucosa harbors IL-33⁺PI16⁺ fibroblasts in the reticular layer of connective tissue, and Treg cells express MIF and TGFB1 in regenerating human oral mucosa. These results unveil a crucial role of IL-33-expressing oral fibroblasts for modulating inflammation in healing wounds via Treg cell activation.

The septotemporal axis of the hippocampus separates it into domains with unique molecular, cellular, downstream connectivity, and behavioral profiles, and yet very little is known about the ontogenesis of these highly specialized subcircuits. Here, we use viral tracing, optogenetic-assisted patch clamping, chemogenetics, and behavior in mice to examine changes in domain-defined hippocampus efferent projections from postnatal day (P)10 to P60. We find distinct anatomical and synaptic developmental signatures in ventral and intermediate CA1 downstream connectivity, with unique contributions to the prelimbic and infralimbic subregions of the medial prefrontal cortex (mPFC). Juvenile inhibition of the ventral and intermediate CA1-mPFC pathways leads to opposing modulation of adult cognitive flexibility, establishing a sex- and pathway-specific sensitive period preceding the stabilization of CA1-mPFC synaptic transmission. Our data elucidate domain- and target-defined postnatal maturation of hippocampus efferents, indicating juvenility as a CA1-mPFC sensitive period with crucial implications for early life influences on adult cognition.

Although macaques and marmosets are both primates of choice for studying the brain mechanisms of cognition, they differ in key aspects of anatomy and behavior. Interestingly, a recent connectomic analysis revealed that strong top-down projections from the prefrontal cortex to the posterior parietal cortex, present in macaques and important for executive function, are absent in marmosets. Here, we propose a consensus mapping that bridges the two species' cortical atlases and allows for direct area-to-area comparison of their connectomes, which are then used to build comparative computational large-scale modeling of the frontoparietal circuit for working memory. The macaque model exhibits resilience against distractors, a prerequisite for normal working memory function. By contrast, the marmoset model predicts a sensitivity to distractibility commonly observed behaviorally in this species. Surprisingly, this contrasting trend can be swapped by rescaling intrafrontal and frontoparietal connection weights and offers a credible prediction to the marmoset's behavior in this specific task.

Promoter-proximal pausing of RNA polymerase II (Pol II) primes genes for rapid activation, yet how Pol II dynamics are temporally organized in adult stem cells to enable fast and flexible responses to environmental cues remain unknown. To address this, we developed sciCUT&Tag2in1 for joint profiling of Pol II and histone modifications in single cells. By profiling over 200,000 CD34⁺ hematopoietic stem cells (HSCs) and progenitors, we identify a Pol II regulatory cascade that directs the response to granulocyte colony-stimulating factor (G-CSF)-induced inflammatory stress. HSCs are activated by elevated Pol II occupancy and reduced Polycomb repression of immune response genes. Lineage commitment proceeds through sequential modes of Pol II activation, beginning with rapid pause-and-release genes, followed by slower initiate-and-release of Polycomb-repressed targets. sciCUT&Tag2in1 defines the temporal logic of how adult stem cells use paused Pol II to enable flexible lineage decisions, providing a powerful tool for studying the intersection of development, inflammation, and disease.

Nucleoside diphosphate kinase (Ndk) is a ubiquitous enzyme that maintains the cellular nucleoside triphosphate (NTP) pool and participates in many other pathways of eukaryotes and prokaryotes. Here, we show that in Escherichia coli, Ndk is regulated by dephosphorylation of its phosphohistidine intermediate via the phosphatase SixA, thereby inhibiting nucleotide phosphoryl transfer activity. We further show that loss of this regulation alters the metabolic state of E. coli in low-nutrient conditions and reduces survival in long-term stationary phase. Similar regulation of Ndk by a phosphohistidine phosphatase has been reported previously for human cells, although the molecular interactions differ. The prevalence of SixA and Ndk orthologs in prokaryotes and the appearance of this regulatory mechanism in both E. coli and humans suggest that phosphohistidine phosphatase-mediated control of nucleoside diphosphate kinases may be widespread.

Disruption of the blood-brain barrier (BBB) increases vascular permeability and promotes neuroinflammation, contributing to Alzheimer's disease (AD) progression. However, the molecular drivers of BBB dysfunction and neuroinflammation in AD remain poorly defined. Here, we identify angiopoietin-2 (ANGPT2) as a central mediator of BBB breakdown and AD progression. Transcriptomic analyses of human AD brains revealed elevated ANGPT2 expression in endothelial cells correlating with disease severity. In 5xFAD mice, endothelial-specific Angpt2 deletion reduced β-amyloid deposition, while Angpt2 overexpression via an adeno-associated viral vector exacerbated the plaque burden. Mechanistically, ANGPT2 suppression of TIE2 signaling increased vascular leakage and fibrin deposition, triggering microglial activation and neuroinflammatory responses that accelerated disease progression. Single-nucleus transcriptomic analyses further revealed Angpt2-driven microglial dysfunction and neuronal impairment consistent with memory deficits observed in behavioral assays. These findings establish ANGPT2 as a critical driver of BBB dysfunction and neuroinflammation in AD and highlight its therapeutic potential.