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Molecular Cancer Oct 2023Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the...
Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays a crucial role in remodeling the tumor microenvironment (TME). Here, through the integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups of CAFs and described their spatial distribution characteristics. Additionally, the analysis of single-cell RNA sequencing (scRNA-seq) data from three additional common cancer types and two newly generated scRNA-seq datasets of rare cancer types, namely epithelial-myoepithelial carcinoma (EMC) and mucoepidermoid carcinoma (MEC), expanded our understanding of CAF heterogeneity. Cell-cell interaction analysis conducted within the spatial context highlighted the pivotal roles of matrix CAFs (mCAFs) in tumor angiogenesis and inflammatory CAFs (iCAFs) in shaping the immunosuppressive microenvironment. In patients with breast cancer (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity in facilitating cancer cell proliferation, promoting epithelial-mesenchymal transition (EMT), and contributing to the establishment of an immunosuppressive microenvironment. Furthermore, a scoring system based on iCAFs showed a significant correlation with immune therapy response in melanoma patients. Lastly, we provided a web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for the research community to investigate CAFs in the context of pan-cancer.
Topics: Humans; Cancer-Associated Fibroblasts; Tumor Microenvironment; Carcinoma; Epithelial-Mesenchymal Transition; Single-Cell Analysis; Fibroblasts
PubMed: 37833788
DOI: 10.1186/s12943-023-01876-x -
Nature Communications Dec 2023Single-cell and spatial technologies that profile gene expression across a whole tissue are revolutionizing the resolution of molecular states in clinical samples....
Single-cell and spatial technologies that profile gene expression across a whole tissue are revolutionizing the resolution of molecular states in clinical samples. Current commercially available technologies provide whole transcriptome single-cell, whole transcriptome spatial, or targeted in situ gene expression analysis. Here, we combine these technologies to explore tissue heterogeneity in large, FFPE human breast cancer sections. This integrative approach allowed us to explore molecular differences that exist between distinct tumor regions and to identify biomarkers involved in the progression towards invasive carcinoma. Further, we study cell neighborhoods and identify rare boundary cells that sit at the critical myoepithelial border confining the spread of malignant cells. Here, we demonstrate that each technology alone provides information about molecular signatures relevant to understanding cancer heterogeneity; however, it is the integration of these technologies that leads to deeper insights, ushering in discoveries that will progress oncology research and the development of diagnostics and therapeutics.
Topics: Humans; Female; Tumor Microenvironment; Biomarkers, Tumor; Breast Neoplasms; Gene Expression Profiling; Transcriptome; Single-Cell Analysis
PubMed: 38114474
DOI: 10.1038/s41467-023-43458-x -
World Journal of Gastroenterology Jan 2024Esophageal intramural pseudodiverticulosis (EIPD) is a disease of unknown pathogenesis characterized by usually systemic, cystic dilatation of the excretory ducts of... (Review)
Review
Esophageal intramural pseudodiverticulosis (EIPD) is a disease of unknown pathogenesis characterized by usually systemic, cystic dilatation of the excretory ducts of esophageal submucosal glands. In this article, I review the epidemiology, clinical manifestations, endoscopic findings, esophagographic findings, and histopathology of EIPD. I also discuss the etiology and possible pathogenesis of EIPD based on my experiences with this disease and a review of the literature. EIPD usually presents with dysphagia in middle-aged individuals. It is often complicated with secondary infections, most commonly candidiasis. On esophagography, EIPD is delineated as small, multiple, flask-shaped outward projections within the esophageal wall. In recent years, EIPD has been mainly diagnosed by endoscopic findings of multiple, localized, small mucosal depressions. The orifices of the "pseudodiverticula" periodically open and close, and excrete mucus onto the mucosal surface. On histopathological examination, the luminal surface of dilated ducts in EIPD is covered by multilayered, hyperplastic epithelial cells, but myoepithelial cells in the glandular acini are well preserved. Treatment of EIPD is usually symptomatic therapy, and prevention of the infectious complications is important. The etiology and pathogenesis of EIPD are largely unknown, but functional abnormalities of autonomic nerve fibers innervating the esophageal glands likely play an important role, since the structures of the glands are basically preserved in this disease.
Topics: Middle Aged; Humans; Diverticulum, Esophageal; Deglutition Disorders; Diverticulum; Mucous Membrane; Esophageal Stenosis
PubMed: 38312118
DOI: 10.3748/wjg.v30.i2.137 -
IScience Oct 2023Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by lymphocytic infiltration and exocrine dysfunction, particularly affecting the salivary...
Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by lymphocytic infiltration and exocrine dysfunction, particularly affecting the salivary gland (SG). We employed single-cell RNA sequencing to investigate cellular heterogeneity in 11 patients with pSS and 5 non-SS controls. Notably, patients with pSS exhibited downregulated SOX9 in myoepithelial cells, potentially associated with impaired epithelial regeneration. An expanded ACKR1 endothelial subpopulation in patients with pSS suggested a role in facilitating lymphocyte transendothelial migration. Our analysis of immune cells revealed expanded IGHD naive B cells in peripheral blood from patients with pSS. Pseudotime trajectory analysis outlined a bifurcated differentiation pathway for peripheral B cells, enriching three subtypes (VPREB3 B, BANK1 B, CD83 B cells) within SGs in patients with pSS. Fibroblasts emerged as pivotal components in a stromal-immune interaction network, potentially driving extracellular matrix disruption, epithelial regeneration impairment, and inflammation. Our study illuminates immune and stromal cell heterogeneity in patients with pSS, offering insights into therapeutic strategies.
PubMed: 37810210
DOI: 10.1016/j.isci.2023.107943 -
International Journal of Oral Science Sep 2023Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity...
Pleomorphic adenoma (PA) is the most common benign tumour in the salivary gland and has high morphological complexity. However, the origin and intratumoral heterogeneity of PA are largely unknown. Here, we constructed a comprehensive atlas of PA at single-cell resolution and showed that PA exhibited five tumour subpopulations, three recapitulating the epithelial states of the normal parotid gland, and two PA-specific epithelial cell (PASE) populations unique to tumours. Then, six subgroups of PASE cells were identified, which varied in epithelium, bone, immune, metabolism, stemness and cell cycle signatures. Moreover, we revealed that CD36 myoepithelial cells were the tumour-initiating cells (TICs) in PA, and were dominated by the PI3K-AKT pathway. Targeting the PI3K-AKT pathway significantly inhibited CD36 myoepithelial cell-derived tumour spheres and the growth of PA organoids. Our results provide new insights into the diversity and origin of PA, offering an important clinical implication for targeting the PI3K-AKT signalling pathway in PA treatment.
Topics: Humans; Adenoma, Pleomorphic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Transcriptome; Myoepithelioma
PubMed: 37679344
DOI: 10.1038/s41368-023-00243-2 -
Normal and Sjogren's syndrome models of the murine lacrimal gland studied at single-cell resolution.Proceedings of the National Academy of... Oct 2023The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the...
The lacrimal gland is of central interest in ophthalmology both as the source of the aqueous component of tear fluid and as the site of autoimmune pathology in the context of Sjogren's syndrome (SjS). To provide a foundational description of mouse lacrimal gland cell types and their patterns of gene expression, we have analyzed single-cell transcriptomes from wild-type (Balb/c) mice and from two genetically based SjS models, and (nonobese diabetic), and defined the localization of multiple cell-type-specific protein and mRNA markers. This analysis has uncovered a previously undescribed cell type, Car6+ cells, which are located at the junction of the acini and the connecting ducts. More than a dozen secreted polypeptides that are likely to be components of tear fluid are expressed by acinar cells and show pronounced sex differences in expression. Additional examples of gene expression heterogeneity within a single cell type were identified, including a gradient of Claudin4 along the length of the ductal system and cell-to-cell heterogeneity in transcription factor expression within acinar and myoepithelial cells. The patterns of expression of channels, transporters, and pumps in acinar, Car6+, and ductal cells make strong predictions regarding the mechanisms of water and electrolyte secretion. In and lacrimal glands, distinctive changes in parenchymal gene expression and in immune cell subsets reveal widespread interferon responses, a T cell-dominated infiltrate in the model, and a mixed B cell and T cell infiltrate in the model.
Topics: Female; Mice; Male; Animals; Sjogren's Syndrome; Lacrimal Apparatus; Mice, Inbred MRL lpr; Mice, Inbred NOD; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 37812717
DOI: 10.1073/pnas.2311983120 -
Biology Oct 2023The muscular systems of echinoderms play important roles in various physiological and behavioral processes, including feeding, reproduction, movement, respiration, and... (Review)
Review
The muscular systems of echinoderms play important roles in various physiological and behavioral processes, including feeding, reproduction, movement, respiration, and excretion. Like vertebrates, echinoderm muscle systems can be subdivided into two major divisions, somatic and visceral musculature. The former usually has a myoepithelial organization, while the latter contains muscle bundles formed by the aggregation of myocytes. Neurons and their processes are also detected between these myoepithelial cells and myocytes, which are capable of releasing a variety of neurotransmitters and neuropeptides to regulate muscle activity. Although many studies have reported the pharmacological effects of these chemical messengers on various muscles of echinoderms, there has been limited research on their receptors and their signaling pathways. The muscle physiology of echinoderms is similar to that of chordates, both of which have the deuterostome mode of development. Studies of muscle regulation in echinoderms can provide new insights into the evolution of myoregulatory systems in deuterostomes.
PubMed: 37887059
DOI: 10.3390/biology12101349 -
Cureus Jul 2023Pleomorphic adenomas (PA) are the most common benign salivary gland tumors. They arise from the major salivary glands, as well as the minor salivary glands. They may... (Review)
Review
Pleomorphic adenomas (PA) are the most common benign salivary gland tumors. They arise from the major salivary glands, as well as the minor salivary glands. They may arise rarely from the palate, oral cavity, neck, and nasal cavity also. Yet, the fourth, fifth, and sixth decades of life are the most common for them to manifest. Forty percent of them occur in males and 60% in females. It is a benign mixed tumor, which has three components: an epithelial component, a myoepithelial cell component, and a mesenchymal component. A fibrous capsule separates these cells from the surrounding tissues. It generally presents as a slowly progressing painless swelling, which is well-delineated, nonsymptomatic, and not involving the facial nerve. Salivary gland tumors can be accurately diagnosed before surgery using fine-needle aspiration (FNA), ultrasonography (USG), and computed tomography (CT) scan. Calponin, cluster of differentiation 9 (CD9), glial fibrillary acidic protein (GFAP), Mcl-2, metastasis suppressor gene (NM23), p63, S-100, smooth muscle actin (SMA), and SRY-box transcription factor 10 (SOX10) exhibit the majority of the positive reactions in pleomorphic adenomas. The diagnostic marker pleomorphic adenoma gene 1 (PLAG1) is frequently employed since it is specific for pleomorphic adenoma. Although benign, these epithelial tumors have a propensity to recur and undergo malignant transformation if incompletely excised, leading to increased morbidity in these patients. A review of the consensus guidelines and literature was conducted, and the online literature on the subject from 2002 was included. This article is not a complete review of all the available literature; rather, it is a comprehensive review of the topic.
PubMed: 37614271
DOI: 10.7759/cureus.42311