Biology subjects

Zhao, Q.

Publications and source records attributed to Zhao, Q..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

A Novel HIF-2α/ARNT Signaling Pathway Protects Against Microvascular Dysfunction and heart failure After Myocardial Infarction

Myocardial infarction (MI) significantly compromises the integrity of the cardiac microvascular endothelial barrier, leading to enhanced leakage and inflammation that contribute to the progression of heart failure. While HIF2 is highly expressed in cardiac endothelial cells (ECs) under hypoxic conditions, its role in regulating microvascular endothelial barrier function during MI is not well understood. In this study, we utilized mice with a cardiac-specific deletion of HIF2, generated through an inducible Cre (Cdh5Cre-ERT2) recombinase system. These mice exhibited no apparent phenotype under normal conditions. However, following left anterior descending (LAD) artery ligation-induced MI, they showed increased mortality associated with enhanced cardiac vascular leakage, inflammation, worsened cardiac function, and exacerbated heart remodeling. These outcomes suggest a protective role for endothelial HIF2 in response to cardiac ischemia. Parallel investigations in human cardiac microvascular endothelial cells (CMVECs) revealed that loss of ecHif2 led to diminished endothelial barrier function, characterized by reduced tight-junction protein levels and increased cell death, along with elevated expression of IL6 and other inflammatory markers. These effects were substantially reversed by overexpressing ARNT, a critical dimerization partner for HIF2 during hypoxia. Additionally, ARNT deletion also led to increased CMVEC permeability. Interestingly, ARNT, rather than HIF2 itself, directly binds to the IL6 promoter to suppress IL6 expression. Our findings demonstrate the critical role of endothelial HIF2 in response to MI and identify the HIF2/ARNT axis as a transcriptional repressor, offering novel insights for developing therapeutic strategies against heart failure following MI.

cell biology↗

bioRxiv2023

Cryo-EM of α-tubulin isotype containing microtubules revealed a contracted structure of α4A/β2A microtubules

Microtubules are hollow /{beta}-tubulin heterodimeric polymers playing critical roles in cells. In vertebrates, both - and {beta}-tubulin have multiple isotypes encoded by different genes, which are intrinsic factors in regulating microtubule functions. However, structures of microtubules composed of different tubulin isotypes, especially -tubulin isotypes, remain largely unknown. Here, we purified recombinant tubulin heterodimers composed of different mouse -tubulin isotypes, including 1A, 1C and 4A, with {beta}-tubulin isotype {beta}2A. We further assembled and determined the cryo-electron microscopy (cryo-EM) structures of 1A/{beta}2A, 1C/{beta}2A, and 4A/{beta}2A microtubules. Our structural analysis demonstrated that 4A/{beta}2A microtubules exhibit a longitudinal contraction between tubulin interdimers compared with 1A/{beta}2A and 1C/{beta}2A microtubules. Collectively, our findings reveal that -tubulin isotype composition could tune microtubule structures, and also provide evidence for the "tubulin code" hypothesis.

biophysics↗

bioRxiv2023

Aberration modeling in deep learning for volumetric reconstruction of light-field microscopy

Optical aberration is a crucial issue in optical microscopes, which fundamentally limits the practical imaging performance. As a commonly encountered one, spherical aberration is introduced by the refractive index mismatches between samples and environments, which will cause problems like low contrast, blurring, and distortion in imaging. Light-field microscopy (LFM) has recently emerged as a powerful tool for fast volumetric imaging. The appearance of spherical aberration in LFM will cause large changes of the point spread function (PSF) and thus greatly affects the imaging performance. Here, we propose the aberration-modeling view-channel-depth (AM-VCD) network for LFM reconstruction, which can well mitigate the influence of large spherical aberration. By quantitatively estimating the spherical aberration in advance and modeling it in the network training, the AM-VCD can obtain aberration-corrected high-speed visualization of three-dimensional (3D) processes with uniform spatial resolution and real-time reconstruction speed. Without any hardware modification, our method provides a convenient way to directly observe the 3D dynamics of samples in solution. We demonstrate the capability of AM-VCD under a large refractive index mismatch with volumetric imaging of a large-scale fishbone of largemouth bass. We further investigate the capability of AM-VCD in real-time volumetric imaging of dynamic zebrafish for tracking neutrophil migration.

bioengineering↗

bioRxiv2023

Region-Based Epigenetic Clock Design Improves RRBS-Based Age Prediction

Recent studies suggest that epigenetic rejuvenation can be achieved using drugs that mimic calorie restriction and techniques such as reprogramming induced rejuvenation. To effectively test rejuvenation in vivo, mouse models are the safest alternative. However, we have found that the recent epigenetic clocks developed for mouse reduced-representation bisulphite sequencing (RRBS) data have significantly poor performance when applied to external datasets. We show that the sites captured and the coverage of key CpGs required for age prediction vary greatly between datasets, which likely contributes to the lack of transferability in RRBS clocks. To mitigate these coverage issues in RRBS-based age prediction, we present two novel design strategies that use average methylation over large regions rather than individual CpGs, whereby regions are defined by sliding windows (e.g. 5 kb), or density-based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs) compared to published individual-CpG-based techniques when applied to external datasets. The RegBCs are also more robust when applied to low coverage data and detect a negative age acceleration in mice undergoing calorie restriction. Our RegBCs offer a proof of principle that age prediction of RRBS datasets can be improved by accounting for multiple CpGs over a region, which negates the lack of read depth currently hindering individual-CpG-based approaches.

bioinformatics↗

bioRxiv2023

Prion-like characteristics of Hepatitis E virus ORF3 protein are associated with virus release and pathogenesis

Hepatitis E virus (HEV) is a common causative agent of acute hepatitis. Due to the shortage of efficient in vitro model, the viral assembly and release processes are still poorly understood. In this study, we found that ORF3, an HEV structural protein showed prion-like properties. The prion domain (PrD) of yeast prion Sup35 could be functionally replaced by HEV-ORF3 and its candidate PrD (cPrD). A single amino acid substitution in the cPrD reduced the aggregation propensity of ORF3 and blocked the function of ORF3 in enhancing the stability of microtubules in HEV-infected cells, thus blocking virion release from the infected cells and resulting in reduced HEV pathogenicity in Mongolian gerbils. These data suggest that HEV-ORF3 is a novel functional prion-like protein which assembles into a filamentous structure for virion release, supporting the hypothesis that the self-propagating properties of prion proteins are widely exploited as epigenetic information carriers in nature.

microbiology↗

bioRxiv2023

DNA G-quadruplex is a transcriptional control device that regulates memory

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here we report that DNA G-quadruplex (G4-DNA) accumulates in neurons in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation. One-Sentence SummaryG4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.

neuroscience↗

bioRxiv2023

IL-15 enhances functional properties and responses of CD28-negative CD4+ cytotoxic T cells expanded in Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder that results in an attack by bodys immune system of its own tissues, causing chronic inflammation and tissue damage. T cells play a key role in the pathogenesis of SLE, as they secrete pro-inflammatory cytokines as well as mediate direct effects on target tissues. Recently, CD4-positive T cells with cytotoxic potential were showed to be involved in autoimmune disease progression and tissue damage. However, whether this cell type expands and plays effector functions in SLE patients remain to be elucidated. Analyzing single-cell RNA sequencing (scRNA-Seq) data and flow cytometry data, we find that cytotoxic CD4+CD28- T cells are present in SLE patients. We also show that these cells expand most prominently in patients affected by lupus nephritis, and they exhibit cytotoxic activity against human renal glomerular endothelial cells in vitro. In addition, our study suggests that Interleukin-15 (IL-15) promotes the expansion, proliferation and cytotoxic function of CD4+CD28- T cells in SLE patients. Tofacitinib, a selective JAK3 inhibitor, inhibits the effect of IL-15 on CD4+CD28- T cells. Together, our study clearly demonstrated that CD4+ CD28- T cells characterized by proinflammatory properties and cytolytic function expand in SLE patients. The pathogenic potential of these CD4+ CD28- T cells is driven by IL-15/IL-15R/JAK3/STAT5 signaling pathway, which may open new avenues for therapeutic intervention to prevent progression of SLE patients.

immunology↗

bioRxiv2022

Tumor Segmentation using temporal Independent Component Analysis for DCE-MRI

In this study, we developed the temporal independent component analysis (tICA) to solve the partial volume effect (PVE) in canine brain tumor segmentation. The performance of the tICA is compared to that of spatial ICA (sICA) and an expert manual delineation of tumors based on three criteria: percent volume overlap or Dice coefficient, and percent volume difference. Seven in vivo DCE-MRI datasets of spontaneously occurring canine brain tumors were acquired on a 3 Tesla MRI system. The mean value of percent volume overlap (76.00%) between sICA and manual segmentation is lower than that between tICA and manual segmentation, which is 81.11%. In conclusion, the performance of the two ICA methods for segmenting tumors is very close to that of the expert delineation method. However, the tICA has the advantage over the sICA method in its ability to separate independent tissue signals in a voxel containing different types of tissues.

bioinformatics↗

bioRxiv2022

Indole produced during dysbiosis mediates host-microorganism chemical

An imbalance of the gut microbiota, termed dysbiosis, has a substantial impact on host physiology. However, the mechanism by which host deals with gut dysbiosis to maintain fitness remains largely unknown. In C. elegans, E. coli, which is its bacterial diets, proliferates in its intestinal lumen during aging. Here, we demonstrate that progressive intestinal proliferation of E. coli activates the transcription factor DAF-16, which is required for maintenance of longevity and organismal fitness in worms with age. DAF-16 up-regulates two lysozymes lys-7 and lys-8, thus limiting the bacterial accumulation in the gut of worms during aging. During dysbiosis, the levels of indole produced by E. coli are increased in worms. Indole is involved in the activation of DAF-16 by TRPA-1 in neurons of worms. Our finding demonstrates that indole functions as a microbial signal of gut dysbiosis to promote fitness of the host.

biochemistry↗

bioRxiv2022

Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of this gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, MSCs were genetically modified to produce mutant {beta}-galactosidase ({beta}-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can entrance into cell and selectively trigger the NO release from genetically engineered MSCs (eMSCs) in the presence of {beta}-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells. SignificanceGaseous signaling molecules (GSMs), such as nitric oxide (NO), hold tremendous potential in regenerative medicine and tissue engineering. However, the delivery of GSMs with stem cells to target tissues or organs in response to demand has never been reported. This study designed engineered mesenchymal stem cells (eMSCs) that produce mutant {beta}-galactosidase ({beta}-GALH363A) and trigger NO release when the NO prodrug is systemically administered, which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs in a mouse model of acute kidney injury (AKI). This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/519950v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1d8f4e4org.highwire.dtl.DTLVardef@b5e548org.highwire.dtl.DTLVardef@1dff1edorg.highwire.dtl.DTLVardef@184130e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2022

Endometrial adhesion G protein-coupled receptors are dynamically expressed across the menstrual cycle and expression is altered by ovarian stimulation

Ovarian stimulation (OS), utilized for the development of multiple ovarian follicles for IVF, induces supraphysiologic levels of E2 and an early rise in P4 that disrupt endometrial differentiation and decreases implantation rates or result in placental insufficiency and pregnancy complications. To improve pregnancy rates and reduce the risk of pregnancy complications associated with IVF, it is crucial to advance our molecular understanding of the molecular regulation of endometrial differentiation. Previous studies from our laboratory suggest G protein-coupled receptors (GPCRs) are important regulators of endometrial differentiation. To investigate this further, using a retrospective dataset, we identified all GPCRs expressed across the proliferative and secretory phase of the menstrual cycle and found that many members of the adhesion G protein-coupled receptor (ADGR) family are dynamically expressed. For each ADGR subfamily exhibiting differentially-expressed genes across the cycle, their expression was investigated by RT-PCR in the non-pregnant mouse uterus and decidua on E7.5 of pregnancy. For those genes expressed in the E7.5 decidua, their expression was further quantified by qPCR across early mouse pregnancy. The RT-PCR screen revealed expression of 13 ADGRs (4 of the 9 subfamilies) in E7.5 decidua and among these genes, many were differentially expressed between E0.5 and E5.5 or 6.5 and between E5.5 and E6.5. The dynamic expression of the ADGRs across the menstrual cycle and in early mouse pregnancy, suggests these ADGRs are E2- and/or P4-regulated genes. We therefore hypothesized that for these ADGR genes, mRNA expression would be disrupted in an OS cycle. This hypothesis was tested on endometrial biopsies collected in the secretory phase from prospective cohorts of women in natural and OS cycles. Consistent with the retrospective dataset, our data revealed that members of the ADGR gene family are expressed in the secretory phase of the natural menstrual cycle and for the first time, we show that their expression is altered by ovarian stimulation.

cell biology↗

bioRxiv2022

Comparative genomic analysis between Leonurus japonicus and Leonurus sibiricus

Leonurus japonicus Houtt. is an important medicinal plant in East Asia and is now widely recognized for its role in treating cerebral apoplexy and lowering blood lipids. Here, we report two sets of chromosome-level genome sequences for leonurine-producing Leonurus japonicus and for its closely related species leonurine-free Leonurus sibiricus, where 99.78% of 518.19 Mb of L. japonicus was assembled into ten pseudochromosomes with a contig N50 of 17.62 Mb and 99.33% of 472.29 Mb of L. sibiricus was assembled into nine pseudochromosomes with a contig N50 of 13.29 MB. The reference genomes of Leonurus will accelerate the decoding of novel bioactive molecules in medicinal plants, especially in the Lamiaceae family.

plant biology↗

bioRxiv2022

Bone Marrow- and Umbilical Cord-Derived Mesenchymal Stem Cell Secretome Alters Gene Expression and Upregulates Motility of Human Endometrial Stromal Cells

IntroductionCyclic regeneration of the endometrium, and its repair after parturition or injury, are crucial for successful reproduction. Mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSC) and umbilical cord (UC-MSC) facilitate tissue repair via their secretome, which contains growth factors and cytokines that promote wound healing. Despite the implication of MSCs in endometrial regeneration and repair, the mechanisms remain unclear. This study tested the hypothesis that the secretome of MSCs from human BM and UC upregulates human endometrial stromal cell (HESC) proliferation, migration and invasion, and activates pathways to increase HESC motility. MethodsMSCs were purchased from ATCC (BM-MSC-1) and cultured from the BM aspirate of three healthy female donors (BM-MSC-2-4), and from umbilical cords of two healthy male term infants (UC-MSC-1-2). Indirect co-culture of MSCs and hTERT-immortalized HESCs via a transwell system studied the effect of the BM-MSC and UC-MSC secretome on HESC proliferation, migration, and invasion. To study the effect of the MSC secretome on HESC gene expression, HESCs were exposed to the BM-MSC secretome via indirect co-culture for 24 h. Total RNA was extracted from HESCs for RNA sequencing (RNA-Seq). Differentially expressed genes (DEG) and significantly altered pathways were identified. MSigDB was used to identify the top 15 enriched biological pathways (padj < 0.05). RT-qPCR was performed to validate changes in mRNA expression of DEG common to both BM-MSC exposures. Given robust upregulation of CCL2 mRNA expression in HESCs exposed to the BM- and UC-MSC secretomes, transwell migration and invasion assays were performed to determine the effect of recombinant CCL2 on HESC motility. Statistical significance was defined as p<0.05. ResultsIndirect co-culture of HESCs with BM- or UC-MSCs resulted in significant increase in HESC migration and invasion regardless of the source of MSCs. However, effects on cellular proliferation varied among the MSC donors. Exposure of HESCs to the secretome of BM-MSCs changed the expression of 10,139 genes with FDR < 0.05. There was overlap among 4350 genes between HESCs exposed to BM-MSC-1 and BM-MSC-2. Within four biological pathways enriched in HESCs, 4 genes (CCL2, HGF, PLAU, and BDKRB2) were differentially expressed in HESCs that had been cocultured with BM-MSC-1 and BM-MSC-2. qRT-PCR showed significantly increased mRNA expression of CCL2 in HESCs exposed to BM-MSC-1 (5-fold) and BM-MSC-2 (7.7-fold). In contrast, the increase in HGF expression was significant after exposure to BM-MSC-2 (1.8-fold) but not BM-MSC-1. Exposure to the UC-MSC secretome had similar effects on HESC-derived CCL2 and HGF levels. CCL2 expression was significantly increased (6.5-fold) by UC-MSC-2 but not by UC-MSC-1; HGF expression was significantly increased (1.6-fold) by UC-MSC-2 but not by UC-MSC-1. Validation studies indicated that exposure to recombinant CCL2 for 48 hours significantly increased HESC migration (1.2-fold) and invasion (1.4-fold). These data suggest that CCL2 is a key factor in mediating MSC-induced HESC motility. ConclusionIncreased HESC motility by the secretome of BM- and UC-MSC appears to be mediated by paracrine and autocrine mechanisms, in part by upregulated CCL2 expression in HESC. Together, our data support the potential for leveraging the MSC secretome as a novel cell-free therapy in the treatment of disorders of endometrial regeneration.

cell biology↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

Proteomic profiling reveals lysosomal heterogeneity in association with longevity

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with different longevity mechanisms. We further discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we discovered lysosomal heterogeneity across tissues as well as the specific enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity at different levels and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk and organism longevity.

cell biology↗

bioRxiv2022

Hypodermal ribosome synthesis inhibition induces a nutrition-uncoupled organism-wide growth quiescence

Inter-organ communication is a key aspect of multicellular organismal growth, development, and homeostasis. Importantly, cell-non-autonomous inhibitory cues that limit tissue specific growth alterations are poorly characterized due to limitations of cell ablation approaches. Here, we report a robust system to investigate nutrition-independent organism-wide growth coordination by modulating ribosome biogenesis at distinct steps in a tissue-specific and reversible fashion in Caenorhabditis elegans. We find an organism-wide growth quiescence response upon suppression of ribosome synthesis either by depletion of an RNA polymerase I (Pol I) subunit or either of two critical ribosome biogenesis factors, RRB-1 and TSR-2, which are the chaperone proteins required for assembly of ribosomal proteins, RPL-3 and RPS-26, respectively. The observed organism-wide growth checkpoint is independent of the nutrition-dependent insulin signaling pathways and is not rescued by daf-16(mu86), a bypass mutation that suppresses the starvation-induced quiescence response. Upon systematically exploring tissues involved in this process, we find that inhibition of hypodermal ribosome synthesis is sufficient to trigger an organism-wide growth quiescence response and leads to organism-wide gene expression changes. At the RNA level, we observe over- and under-expression of several tissue-restricted genes in a wide range of cell types, including touch receptor neurons suggesting inter-organ communication upon hypodermis driven ribosome inhibition. At the protein level, we observed over-expression of secreted proteins (CPR-4, TTR family proteins) as well as an organism-wide reduction both in cytosolic and mitochondrial ribosomal proteins in response to hypodermis RNA Pol I depletion. Finally, we find that dense core vesicle secretion specifically from the hypodermis tissue by the unc-31 gene plays a significant role in mediating the quiescence phenotype. Taken together, these results suggest the presence of a nutrition-independent multicellular growth coordination initiated from the hypodermis tissue.

developmental biology↗

bioRxiv2022

The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae.

The presence of anticancer clerodane diterpenoids is a chemotaxonomic marker for the traditional Chinese medicinal plant Scutellaria barbata, although the molecular mechanisms behind clerodane biosynthesis are unknown. Here, we report a high-quality assembly of the 414.98 Mb genome of S. barbata into thirteen pseudochromosomes. Using phylogenomic and biochemical data, we mapped the plastidial metabolism of kaurene (gibberellins), abietane and clerodane diterpenes in three species of the family Lamiaceae (Scutellaria barbata, Scutellaria baicalensis and Salvia splendens), facilitating the identification of genes involved in the biosynthesis of the clerodanes, kolavenol and isokolavenol. We show that clerodane biosynthesis evolved through recruitment and neofunctionalization of genes from gibberellin and abietane metabolism. Despite the assumed monophyletic origin of clerodane biosynthesis which is widespread in species of the Lamiaceae, our data show distinct evolutionary lineages and suggest polyphyletic origins of clerodane biosynthesis in the family Lamiaceae. Our study not only provides significant insights into the evolution of clerodane biosynthetic pathways in the mint family, Lamiaceae, but also will facilitate the elucidation of anticancer clerodanes biosynthesis and future metabolic engineering efforts to increase the production of these high-value chemicals.

plant biology↗

bioRxiv2022

VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.

immunology↗