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Single-cell analysis of multiple cancer types reveals differences in endothelial cells between tumors and normal tissues.
Endothelial cells (ECs) play an important role in tumor progression. Currently, the main target of anti-angiogenic therapy is the vascular endothelial growth factor (VEGF) pathway. Some patients do benefit from anti-VEGF/VEGFR therapy; however, a large number of patients do not have response or acquire drug resistance after treatment. Moreover, anti-VEGF/VEGFR therapy may lead to nephrotoxicity and cardiovascular-related side effects due to its action on normal ECs. Therefore, it is necessary to identify targets that are specific to tumor ECs and could be applied to various cancer types. We integrated single-cell RNA sequencing data from six cancer types and constructed a multi-cancer EC atlas to decode the characteristic of tumor ECs. We found that tip-like ECs mainly exist in tumor tissues but barely exist in normal tissues. Tip-like ECs are involved in the promotion of tumor angiogenesis and inhibition on anti-tumor immune responses. Moreover, tumor cells, myeloid cells, and pericytes are the main sources of pro-angiogenic factors. High proportion of tip-like ECs is associated with poor prognosis in multiple cancer types. We also identified that prostate-specific membrane antigen (PSMA) is a specific marker for tip-like ECs in all the cancer types we studied. In summary, we demonstrate that tip-like ECs are the main differential EC subcluster between tumors and normal tissues. Tip-like ECs may promote tumor progression through promoting angiogenesis while inhibiting anti-tumor immune responses. PSMA was a specific marker for tip-like ECs, which could be used as a potential target for the diagnosis and treatment of non-prostate cancers.
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Spinal cord regeneration deploys cell-type specific developmental and non-developmental strategies to restore neuron diversity.
A major goal of spinal cord injury research is to develop a path to endogenous regeneration. This approach has been heavily informed by animal models of natural regeneration. An unresolved question is whether these models rebuild the spinal cord exclusively by accessing developmental mechanisms of neuron differentiation. To address this question, we contrasted single-cell gene expression during regeneration with stage-matched controls in the conditionally regenerative frog Xenopus tropicalis. We generated an expanded atlas of neuronal diversity, annotating several previously unidentified neuron classes. From this atlas, we found that the neuron composition of the developing and regenerating spinal cord differ. So do the strategies employed, which favor waves of cell-type specific neurite projection and guidance then proliferative neurogenesis during regeneration. Low levels of early neurogenesis are then compensated by movement of post-mitotic neurons. Our work highlights the contributions of distinct developmental versus regenerative paths to heal post-injury.
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Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier.
The blood-brain barrier (BBB) serves as a crucial vascular specialization, shielding and nourishing brain neurons and glia while impeding drug delivery. Here, we conducted single-cell mRNA sequencing of human cerebrovascular cells from 13 surgically resected glioma samples and adjacent normal brain tissue. The transcriptomes of 103,230 cells were mapped, including 57,324 endothelial cells (ECs) and 27,703 mural cells (MCs). Both EC and MC transcriptomes originating from lower-grade glioma were indistinguishable from those of normal brain tissue, whereas transcriptomes from glioblastoma (GBM) displayed a range of abnormalities. Among these, we identified LOXL2-dependent collagen modification as a common GBM-dependent trait and demonstrated that inhibiting LOXL2 enhanced chemotherapy efficacy in both murine and human patient-derived xenograft (PDX) GBM models. Our comprehensive single-cell RNA sequencing-based molecular atlas of the human BBB, coupled with insights into its perturbations in GBM, holds promise for guiding future investigations into brain health, pathology, and therapeutic strategies.
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Single-cell consequences of X-linked meiotic drive in stalk-eyed flies.
Sex-linked meiotic drivers limit the inheritance of the alternate sex chromosome in the heterogametic sex, subsequently skewing the offspring sex ratio. They consequently have large impacts on genome evolution, adaptation, and the emergence and maintenance of sexually selected traits. Despite this, our understanding of their molecular basis and consequences for gametogenesis and sex chromosome regulation more broadly has focused on a handful of model organisms, primarily Drosophila and mouse, which are not representative of the broad diversity of reproductive modes and drive systems in nature. Here, we employ single-cell RNA sequencing (scRNA-seq) to investigate a sex-linked meiotic driver in the Malaysian stalk-eyed fly, Teleopsis dalmanni. First, we produce a comprehensive single-cell atlas of the male T. dalmanni gonad and identify major testis cell types. We then provide a comprehensive profile of the cellular and transcriptional landscape of the testis, providing evidence for a lack of complete meiotic sex chromosome inactivation and complex trajectory of dosage compensation. Second, by contrasting single-cell expression data between drive and standard testes, we provide insight into the consequences of a meiotic driver for the transcriptomic landscape of the testis and sex chromosome regulation. Importantly, we show that the presence of a meiotic driver does not perturb fundamental patterns of X-linked regulation. Our results provide insight into how the meiotic driver might bias its transmission to the next generation and highlight genes with perturbed expression as a potential consequence of the disruption of spermatogenesis.
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Integrated Profiling Delineated KIF18A as a Significant Biomarker Associated with Both Prognostic Outcomes and Immune Response in Pancreatic Cancer.
PURPOSE: Kinesin family member 18A (KIF18A) is a member of the kinesin-8 family of motor proteins, involved in the progression and metastasis of various tumors. However, its role in pancreatic adenocarcinoma (PAAD) remains unclear. METHODS: To evaluate that role, RNA sequencing datasets, complemented by pertinent clinical metadata, were procured from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) repositories. The protein expression level of KIF18A in PAAD was derived from human protein atlas (HPA) database. The differences in KIF18A expression levels and prognostic related genes were identified through multivariate Cox regression and Lasso regression analysis to construct a prognostic risk model. The Tumor Mutation Burden (TMB), Microsatellite (MSI), immune landscape, mutation landscape and drug sensitivity of high- and low-expression KIF18A groups were assessed in immunotherapy cohorts and KIF18A expression cohorts. Finally, in vitro experiments were conducted to elucidate the molecular function of KIF18A in regulating the malignant behavior of PAAD. RESULTS: KIF18A is highly expressed in PAAD and is closely related to worse clinical stage and poor prognosis. Single cell analysis revealed that KIF18A is mainly expressed in microtubules of tumor cells and participated in mitosis and cell cycle of PAAD. Further analysis revealed that the expression of KIF18A is closely related to TMB, MSI, and immune cell infiltration. In vitro experiments confirmed that KIF18A promotes the proliferation, migration and expression of adhesion molecules in PAAD, and inhibits angiogenesis. In addition, the high expression of KIF18A is positively related to ferroptosis and m6A genes expression, and its high expression is driven by mutated KRAS and TP53. CONCLUSION: This study confirmed that KIF18A can be used as a marker to predict the prognosis and immunotherapy of PAAD, and it participates in the formation of microtubules in PAAD cells and promotes the malignant behavior of PAAD.
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Transcriptional Landscape of Cotton Roots in Response to Salt Stress at Single-cell Resolution.
Increasing soil salinization has led to severe losses of plant yield and quality. Thus, it is urgent to investigate the molecular mechanism of the salt stress response. In this study, we took systematically analyzed cotton root response to salt stress by single-cell transcriptomics technology; 56,281 high-quality cells were totally obtained from 5-days-old lateral root tips of Gossypium arboreum under natural growth and different salt-treatment conditions. Ten cell types with an array of novel marker genes were synthetically identified and confirmed with in situ RNA hybridization, and some specific-type cells of pesudotime analysis also pointed out their potential differentiation trajectory. The prominent changes of cell numbers responding to salt stress were observed on outer epidermal and inner endodermic cells, which were significantly enriched in response to stress, amide biosynthetic process, glutathione metabolism, and glycolysis/gluconeogenesis. Other functional aggregations were concentrated on plant-type primary cell wall biogenesis, defense response, phenylpropanoid biosynthesis and metabolic pathways by analyzing the abundant differentially expressed genes (DEGs) identified from multiple comparisons. Some candidate DEGs related with transcription factors and plant hormones responding to salt stress were also identified, of which the function of Ga03G2153, an annotated auxin-responsive GH3.6, was confirmed by using virus-induced gene silencing (VIGS). The GaGH3.6-silenced plants presented severe stress-susceptive phenotype, and suffered more serious oxidative damages by detecting some physiological and biochemical indexes, indicating that GaGH3.6 might participate in salt tolerance in cotton through regulating oxidation-reduction process. For the first time, a transcriptional atlas of cotton roots under salt stress were characterized at a single-cell resolution, which explored the cellular heterogeneityand differentiation trajectory, providing valuable insights into the molecular mechanism underlying stress tolerance in plants.
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Single-Cell Transcriptomic Analysis of the Immune Response to COVID-19 and Tuberculosis Coinfection.
The immune characteristics and pathological mechanisms of COVID-19 and tuberculosis coinfection are not well understood. Single-cell RNA sequencing has emerged as a powerful tool for dissecting complex immune responses and cellular interactions in infectious diseases. Here, we employed scRNA-seq, combined with laboratory examinations and clinical observations, to elucidate potential mechanisms of immunopathology and protective immunity in coinfected patients. Substantial alterations in immune cell populations in patients with severe coinfection were observed, characterized by severe lymphopenia and massive expansion of myeloid cells. Lymphocytopenia may have resulted from lymphocyte apoptosis and migration. Systemic upregulation of S100 family proteins, mainly released by classical monocytes, might contribute to inflammatory cytokine storm via S100-TLR4-MyD88 signaling pathway in severely coinfected patients. Myeloid cells may contribute to immune paralysis in severe cases through expansion of myeloid-derived suppressor cells and dysregulated dendritic cell function. The immune landscape of T cells in severe patients were featured by dysregulated Th1 response, widespread exhaustion and increased cytotoxic, apoptosis, migration and inflammatory states. We observed increased plasma cells and overexpression of B-cell-activation-related pathways in severe patients. Together, we provide a comprehensive atlas illustrating the immune response to coinfected patients at the single-cell resolution and highlight mechanisms of pathogenesis in severe patients.
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KRT19 is a Promising Prognostic Biomarker and Associates with Immune Infiltrates in Serous Ovarian Cystadenocarcinoma.
BACKGROUND: Ovarian cancer (OV) is the highest prevalent gynecologic tumor with complicated pathogenesis; high-grade serous ovarian cystadenocarcinoma (HGSOC) is the most epidemiological and malignant subtype of OV. Keratin type I cytoskeleton 19 (KRT19) is an intermediate filament protein which plays essential roles in the maintenance of epithelial cells. However, its role in OV remains largely unknown. METHODS: Bioinformatic analysis with various databases was conducted in this study. In details, KRT19 expression was assessed using databases including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO) and Human Protein Atlas (HPA). GO-KEGG and GSEA analysis were performed by R packages. The biological function of KRT19 was analyzed based on the single-cell sequencing information from CancerSEA database. The association of KRT19 expression with immunomodulator and chemokine was predicted via the TISIDB database. RESULTS: The expression of KRT19 was significantly upregulated in ovarian samples compared with normal controls. KRT19 expression was negatively associated with prognosis in OV, and further analysis revealed that KRT19 had promising diagnostic significance in distinguishing OV cancer from normal samples. GO-KEGG and GSEA analysis indicated that KRT19 was associated with multiple biological functions and pathways including epidermis development, apical junction, inflammatory response, and epithelial mesenchymal transition. By using different GEO series, we found that KRT19 was differentially expressed in OV-associated tissues. Furthermore, the increased KRT19 expression was positively correlated with the immune infiltration levels of the most immune cells in OV. CONCLUSION: This study demonstrated that KRT19 is a promising prognosis and diagnosis biomarker that determines cancer progression and is correlated with tumor immune cells infiltration in OV, suggesting being a molecular target for immunotherapies.
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The role of KRT18 in lung adenocarcinoma development: integrative bioinformatics and experimental validation.
Lung adenocarcinoma (LUAD) represents one of the most common subtypes of lung cancer with high rates of incidence and mortality, which contributes to substantial health and economic demand across the globe. Treatment today mainly consists of surgery, radiotherapy, and chemotherapy, but their efficacy in advanced stages is often suboptimal and emphasizes the clear need for new biomarkers and therapeutic targets. Using comprehensive bioinformatics analyses consisting of the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), immune infiltration analysis and functional enrichment analysis, and single-cell analysis, we examined the potential of keratin 18 (KRT18) as a candidate biomarker in advanced LUAD. KRT18 was significantly elevated in LUAD tissue relative to normal adjacent tissue (p < 0.05), and its expression was correlated with poor clinical-pathological features and inferior prognostic outcome. Furthermore, KRT18 expression was associated with several populations of immune cells, suggesting KRT18 may contribute to the local tumor microenvironment and potentially pathways of immune evasion. Survival analysis indicated that elevated KRT18 expression correlated with poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI), reinforcing its legitimacy as a prognostic tool (AUC = 0.846). Importantly, gene enrichment analysis found KRT18-associated genes enriched for pathways associated with lymphocyte differentiation and immune response pathways, which provides mechanistic insight into biological effects attributed to KRT18. Notably, NU.1025 has demonstrated the capability of reversing KRT18-modulated oncogenic features, and targeted therapeutic strategies can be developed moving forward. In conclusion, our data demonstrate that KRT18 has utility as a potential biomarker but may also serve as a therapeutic target in LUAD and merit further investigation into underlying mechanistic functions and potential therapeutic roles in the clinic.
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Single-cell multi-omic atlas and morphogen screening informs midbrain and hindbrain organoid engineering.
Patterning of the neural tube establishes midbrain and hindbrain structures that coordinate motor movement, process sensory input and integrate cognitive functions. Cellular impairment within these structures underlies diverse neurological disorders, and in vitro organoid models promise inroads to understanding development and modeling disease. Here, we use paired single-cell transcriptome and accessible chromatin sequencing to map cell composition and regulatory mechanisms in organoid models of midbrain and hindbrain. We find that existing midbrain organoid protocols generate ventral and dorsal cell types, covering regions including floor plate, dorsal and ventral midbrain and adjacent hindbrain regions. Gene regulatory network inference and transcription factor perturbation resolve mechanisms underlying neuronal differentiation. A single-cell multiplexed patterning screen identifies morphogen concentrations that expand existing organoid models, including conditions generating medulla glycinergic neurons and cerebellum glutamatergic subtypes. Together, the multi-omic atlas and morphogen screen reveal morphogen-regulon relationships guiding region-specific progenitor differentiation towards diverse neuron types of the posterior brain.