Cell Discovery最新文献

Exocrine and endocrine disorders and insufficiency are two major harmful pathological processes in chronic pancreatitis (CP) and can lead to steatorrhea and diabetes. However, there is a lack of reliable clinical classification schemes for evaluating the severity of exocrine and endocrine disorders in CP, and the underlying mechanisms are also unclear. In particular, exosome-based liquid biopsy and classification in CP are lacking. Here, we performed transcriptome sequencing on plasma exosomes from CP patients with different degrees of CP severity. Additionally, we analyzed single-cell sequencing data from pancreatic lesions in CP patients to interpret the classification, and an external cohort was established to verify the classification. Ultimately, we established and preliminarily verified a 3-stage classification system to predict steatorrhea and diabetes onset in CP patients based on the expression of 12 miRNAs in plasma exosomes. A publicly-available online tool implementing this classification system was also developed. Further analysis, in combination with single-cell sequencing data from CP mice, identified exosome-derived miR-24-3p and neutrophil S100A8 as pivotal factors in CP progression. Mechanistically, our findings suggest that downregulated exosome-derived miR-24-3p in CP may lead to the upregulation of its target gene, S100A8, in neutrophils, thus promoting CP-related exocrine and endocrine disorders by activating the fibrotic phenotype of pancreatic stellate cells and inducing inflammation in macrophages, leading to the apoptosis of pancreatic β cells. Together, our work provides a novel exosome-based 3-stage classification system for CP and highlights the role of exosomal miR-24-3p and S100A8 in fibrosis and pancreatic β-cell apoptosis.

Gene fusions are becoming critical oncogenic drivers with potential therapeutic relevance across various cancers. However, their roles and clinical implications in breast cancer remain largely unexplored. In this study, we leveraged a large-scale multiomics cohort and a drug screening platform for breast cancer to systematically profile gene fusions. We identified ADK fusion genes as novel and recurrent drivers in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2‒) breast cancer. Functionally, the most commonly occurring ADK fusion gene, KAT6B::ADK, enhances metastatic potential and confers tamoxifen resistance. Mechanistically, KAT6B::ADK activates ADK kinase activity through liquid‒liquid phase separation, triggering the activation of an integrated stress response signaling pathway. Notably, patient-derived organoids harboring KAT6B::ADK from HR+/HER2‒ breast cancer demonstrate increased sensitivity to ADK inhibitors, underscoring the therapeutic potential of this fusion gene. Our findings establish ADK fusions as therapeutic targets in HR+/HER2‒ breast cancer, offering new avenues for innovative precision treatment strategies in this patient population.

Liver transplantation remains constrained by the scarcity of donor organs and the risks inherent in the procedure, underscoring the urgent need for novel cirrhosis therapies. We developed a protocol to convert human primary hepatocytes into expandable hepatocyte-derived liver progenitor-like cells (HepLPCs), which secrete high levels of matrix metalloproteinases and hepatocyte growth factor. In a thioacetamide-induced rat model of cirrhosis, human HepLPCs demonstrated potent anti-fibrotic properties and promoted liver regeneration. Biodistribution studies revealed that most xenogenic HepLPCs were cleared from the body within one week, suggesting that their therapeutic benefits likely arise from paracrine signaling rather than long-term engraftment. We initiated a first-in-human clinical trial involving nine patients with cirrhosis to evaluate the feasibility and safety of HepLPCs. Preclinical toxicity assessments in 36 crab-eating macaques confirmed the safety of HepLPC treatment. In the clinical trial, nine patients (mean age: 53 years), primarily with HBV-related cirrhosis, received HepLPCs via trans-hepatic arterial infusion without immunosuppressants. No serious adverse event was observed, and the minor adverse events were consistent with those commonly seen in cirrhosis patients. The treatment was well tolerated, with no transfusion reactions or dose-limiting toxicities. While significant changes in Child-Pugh and MELD scores were not observed, some patients showed improvements in liver biochemical parameters, coagulation profiles, and portal hypertension indicators during the six-month follow-up. These findings indicate that HepLPC therapy is safe and feasible, offering a promising new strategy for treating cirrhosis. Further clinical trials are needed to assess its efficacy in patients with decompensated cirrhosis and acute-on-chronic liver failure.

The Tol-Pal system is essential for maintaining outer membrane (OM) stability during cell division in Gram-negative bacteria. The inner membrane complex TolQRA harnesses proton motive force (PMF) to establish transient interactions within the periplasm, thereby coordinating cell envelope remodeling and facilitating OM invagination at division sites. However, the precise mechanism remains unclear. Here, we present cryo-electron microscopy structures of Escherichia coli TolQRA in multiple conformational states at 2.92-3.52 Å resolution, revealing rotary dynamics within the complex. Computational simulations reveal a proton-conductive channel comprising the putative proton-accepting residue Asp23 and the conserved polar residues Thr145 and Thr178, with monitored inter-residue distances providing support for a proton-driven rotary mechanism. Site-directed mutagenesis combined with functional assays validates the AlphaFold-predicted structure of the periplasmic domains of TolR and TolA, and further pinpoints critical residues required for complex function. Together, these findings advance our understanding of TolQRA-mediated proton transduction and offer new avenues for antibiotic drug development.

The role of CD8⁺ tissue-resident memory T (CD8⁺ T_RM) in inflammation is well established. However, the mechanisms by which CD8⁺ T_RM cells are activated in tissues have remained elusive. Here, we show that Leucine zipper-like transcription regulator 1 (LZTR1), a substrate adaptor for cullin3 (CUL3) ubiquitin ligase complex, regulates CD8⁺ T_RM activation and proliferation in cutaneous and colonic epithelia through modulation of major histocompatibility complex class I (MHC-I) expression in an NF-κB1-dependent manner. Mechanistically, LZTR1 modulates MHC-I transcription by regulating co-translational biogenesis of NF-κB1 (p50) in a ubiquitination-independent but proteasome-dependent manner through direct binding with ribosome and proteasome. Loss of LZTR1 leads to suppression of CD8⁺ T_RM activation and proliferation and decreased production of IL-17A with blunting of inflammatory responses in both cutaneous and gut epithelia in vivo. In summary, these data identify LZTR1 as a novel regulator of CD8⁺ T_RM function and provide insights into the mechanisms that drive and maintain CD8⁺ T-cell responses in epithelial-associated autoimmune diseases.