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Integrated multimodal cell atlas of Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.
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A population-scale atlas of blood and tissue in lupus nephritis.
Lupus nephritis (LN), a severe manifestation of Systemic Lupus Erythematosus (SLE), is a heterogeneous disease driven by diverse immune and tissue cell types. We obtained 538K single-cell and 140K single-nuclear profiles from kidney biopsies of 155 LN patients and 30 pre-implantation transplant biopsy controls, along with 325K single-cell blood profiles overlapping many of these patients. We identified key tissue cell types and cell states, and immune cell states; we were able to determine cell states that were tissue specific, and those that were present in the blood. We observed that LN pathological features are significantly associated with cell states using differential gene expression and Covarying Neighborhood Analysis (CNA). These analyses revealed broad changes in cell states associated with irreversible chronic tissue damage. After controlling for the effects of ongoing tissue damage, we observed that expansion of key glomerular and Scar Associated Macrophages (SAMs) populations tracked with increasing inflammatory disease activity. SAMs appear to drive LN fibrosis and, in active disease, infiltrate the glomeruli more than other myeloid cells. These observations strongly support that therapeutic targeting of myeloid populations may offer an as-of-yet unproven strategy to prevent renal inflammation and ongoing kidney damage in LN.
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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics.
Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.
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Deciphering state-dependent immune features from multi-layer omics data at single-cell resolution.
Current molecular quantitative trait locus catalogs are mostly at bulk resolution and centered on Europeans. Here, we constructed an immune cell atlas with single-cell transcriptomics of >1.5 million peripheral blood mononuclear cells, host genetics, plasma proteomics and gut metagenomics from 235 Japanese persons, including patients with coronavirus disease 2019 (COVID-19) and healthy individuals. We mapped germline genetic effects on gene expression within immune cell types and across cell states. We elucidated cell type- and context-specific human leukocyte antigen (HLA) and genome-wide associations with T and B cell receptor repertoires. Colocalization using dynamic genetic regulation provided better understanding of genome-wide association signals. Differential gene and protein expression analyses depicted cell type- and context-specific effects of polygenic risks. Various somatic mutations including mosaic chromosomal alterations, loss of Y chromosome and mitochondrial DNA (mtDNA) heteroplasmy were projected into single-cell resolution. We identified immune features specific to somatically mutated cells. Overall, immune cells are dynamically regulated in a cell state-dependent manner characterized with multiomic profiles.
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[Impact of bone metastasis on the prognosis of lung adenocarcinoma patients treated with third-generation EGFR-TKI and the underlying mechanisms].
Objective: To evaluate the impact of bone metastasis on the prognosis of lung adenocarcinoma patients receiving first-line third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and to explore the potential mechanisms by which bone metastasis contributes to EGFR-TKI resistance. Methods: A retrospective analysis was conducted on the clinical data of 370 EGFR-mutant advanced lung adenocarcinoma patients who received first-line treatment with third-generation EGFR-TKI at the First Affiliated Hospital of Nanjing Medical University from January 2019 to June 2024, with follow-up until June 2024. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without baseline bone metastasis. Survival curves were generated using the Kaplan-Meier method, and differences between groups were assessed by the log-rank test. Univariate and multivariate Cox proportional hazards regression models were applied to identify factors associated with PFS following third-generation EGFR-TKI treatment. Single-cell RNA sequencing (scRNA-seq) was performed on two primary pulmonary tumors and two bone metastatic lesions to characterize transcriptomic differences in cancer cells and immune cells within the tumor microenvironment. Gene ontology (GO) enrichment analysis was applied to identify bone metastasis-specific signaling pathways. Based on immune regulatory genes upregulated in cancer cells from bone metastatic lesions, an immune-regulatory score was constructed using a LASSO-Cox regression model in a training cohort of EGFR-mutant lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA). Patients in both the training cohort and an independent Asian EGFR-mutant lung adenocarcinoma validation cohort were stratified into high-and low-score groups according to the median immune regulatory score, and OS was compared between groups. Results: Among the 370 lung adenocarcinoma patients receiving first-line third-generation EGFR-TKI treatment, 161 patients had baseline bone metastasis [mean age (60±11) years; 70 males], while 209 patients had no baseline bone metastasis [mean age (61±9) years; 80 males]. No significant differences in baseline clinicopathological characteristics were observed between patients with and without bone metastasis (all P>0.05). The median PFS in the bone metastasis group was 27.5 months (95%CI: 22.0-33.1), which was significantly shorter than that in the non-bone metastasis group [59.0 months (95%CI: 32.8-85.1), P<0.001]. The median OS was 46.2 months (95%CI: 40.4-51.9) in the bone metastasis group, whereas the median OS had not yet been reached in the non-bone metastasis group, with a statistically significant difference (P=0.013). Multivariate Cox regression analysis identified bone metastasis as an independent risk factor for PFS (HR=1.74, 95%CI:1.27-2.37, P<0.001). Cancer cells in bone metastatic lesions exhibited upregulation of C-X-C motif chemokine ligand 17 (CXCL17), complement decay-accelerating factor (CD55), interferon regulatory factor 1 (IRF1), E3 ubiquitin-protein ligase pellino homolog 1 (PELI1), solute carrier family 7 member 5 (SLC7A5) and prostaglandin-endoperoxide synthase 2 (PTGS2), which were predominantly enriched in pathways related to immune cell differentiation, chemotaxis, and inflammatory responses. At the immune cell level, lymphoid cells in bone metastatic lesions showed activation of stress response and apoptotic pathways, whereas myeloid cells demonstrated significant activation of cytokine/chemokine signaling and inflammation-related pathways. An immune-regulatory score based on CXCL17, CD55, IRF1, PELI1, SLC7A5, and PTGS2 was constructed. In the TCGA training cohort, the median OS of 41 patients with a high immune-regulatory score was 23.1 months (95%CI: 17.5-28.7), which was significantly shorter than that of patients with a low score [58.5 months (95%CI: 43.0-73.9), P<0.001]. In the independent Asian cohort of 93 EGFR-mutant lung adenocarcinoma patients, the median OS of 46 patients with a high immune-regulatory score was 85.3 months (95%CI: 80.0-not reached), while the median OS in the low-score group was not reached, with a statistically significant difference (P=0.014). Conclusions: Bone metastasis is an adverse prognostic factor for progression-free survival in lung adenocarcinoma patients treated with third-generation EGFR-TKI. Bone metastasis lesions exhibit a distinct immunosuppressive tumor microenvironment in EGFR-mutant advanced lung adenocarcinoma, in which upregulation of immune regulatory genes in cancer cells and dysfunction of immune cells may constitute a potential mechanism underlying resistance to third-generation EGFR-TKI.
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Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma.
UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE: Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
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A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis.
Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.
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MITI minimum information guidelines for highly multiplexed tissue images.
The imminent release of tissue atlases combining multi-channel microscopy with single cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards that guide data deposition, curation and release. We describe a Minimum Information about highly multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and other microscopy data to highly multiplexed tissue images and traditional histology.
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A comprehensive spatial proteome landscape of ectopic lymphoid-like structures in metastatic colorectal cancer reveals specific signatures for predicting clinical outcomes.
We previously generated a global bulk-level proteogenomic atlas of metastatic colorectal cancer (CRC) in a Chinese cohort (CCRC). Using formalin-fixed paraffin-embedded tissues from this cohort, we identified 2095 ectopic lymphoid-like structures (ELSs) across 132 primary tumors. Both lymphoid aggregates (Aggs) and tertiary lymphoid structures (TLSs) were significantly associated with metastasis and clinical outcomes in CRC, in which the spatial and compositional heterogeneity of ELSs and their clinical relevance remain unknown. Here, we upgraded our LCM-MTA platform to version 2.0 for deep spatial proteomics and profiled spatial proteomic landscapes from matched mCRC and non-mCRC cases with comparable baseline clinical features. This analysis revealed pronounced spatial heterogeneity in protein expression, distinguishing ELSs from parenchymal regions in paired tumor and para-carcinoma tissues. Notably, TLSs displayed distinct functional states: mCRC-associated TLSs showed enrichment of anti-tumor immune activation pathways, whereas non-mCRC TLSs were enriched in acute inflammatory response pathways. Based on these findings, we developed a 13-protein TLS signature and scoring system to predict metastasis and prognosis in the CCRC cohort, validated in two independent CPTAC cohorts. We present a comprehensive spatial proteomic map of ELSs in metastatic CRC and identify a TLS-based signature with strong potential for predicting metastasis and clinical outcomes.
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A hybrid epithelial/mesenchymal state in head and neck cancer: A biomarker for survival with differential prognosis by self-reported race.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cause of cancer-related mortality, with racial disparities amplifying the challenges in treatment. Although the relationship between hybrid epithelial/mesenchymal (E/M) states and tumor progression is of interest, no studies have characterized the clinical relevance of hybrid E/M states in head and neck cancer outcomes among self-reported racial cohorts. METHODS: Given the overlap in gene expression between hybrid E/M malignant cells and cancer-associated fibroblasts, we utilized deconvolution of bulk RNA sequencing data from oral cavity and laryngeal squamous cell carcinoma tumors from The Cancer Genome Atlas. We utilized our previously collected single-cell profiles to generate inferred malignant profiles and then scored these for hybrid E/M. We then conducted a survival analysis on overall and disease-free survival among self-reported Black and White Americans. FINDINGS: The hybrid E/M state was differentially associated with head and neck cancer survival by self-reported race and ethnicity, with a stronger association in non-Hispanic Black patients. Black patients with a high hybrid E/M score had a higher risk of death or recurrence (hazard ratio [HR]: 4.18 [95% confidence interval (CI): 2.06, 8.49]) than White patients with a high hybrid E/M score (HR: 1.58 [95% CI: 1.11, 2.26]). CONCLUSION: Our results suggest a complex interplay of social structure, racism, and genetic diversity. We implore researchers to consider the social and biological context contributing to disparities. FUNDING: A.L.M. received support from the National Institute of Minority Health and Health Disparities (K01MD013897 [principal investigator (PI), A.L.M.]). S.V.P. received support from the National Institute of Dental and Craniofacial Research (R01DE032865 [PI, S.V.P.] and R01DE032371 [PI, S.V.P.]).