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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 -
Histopathology Oct 2021Breast lesions with a prominent myoepithelial cell component constitute a heterogeneous group of benign and malignant neoplastic proliferations. These lesions are often... (Review)
Review
Breast lesions with a prominent myoepithelial cell component constitute a heterogeneous group of benign and malignant neoplastic proliferations. These lesions are often dual epithelial-myoepithelial, but may be purely myoepithelial cell in nature. Benign epithelial-myoepithelial lesions typically maintain the morphology and immunophenotype of the normal bilayer epithelial myoepithelial structures. However, the distinction between the two cell components is not always clear-cut in malignant lesions in which the histogenesis of myoepithelial cells remains uncertain. Neoplastic biphasic epithelial-myoepithelial lesions of the breast include adenomyoepithelioma (AME), pleomorphic adenoma and adenoid cystic carcinoma. Four histological patterns of classical AME have been described: tubular, lobulated, spindle-cell and adenosis variants. Overlapping patterns occur and some AMEs display an intraductal papillary pattern that may represent a fifth variant. AME can be benign or malignant. Classical AME may show atypical features, which are not sufficient for the diagnosis of malignancy (atypical AME). Atypical AME is recognised as a lesion of uncertain malignant potential with limited metastatic capability. Based on the histological features, we propose a classification of malignant AME (M-AME) into three variants: M-AME in situ, M-AME invasive and AME with invasive carcinoma. In this review, we provide an overview of myoepithelial lesions of the breast focusing on the classification of AME to improve not only the consistency of reporting but also help to guide further management decision-making.
Topics: Adenomyoepithelioma; Breast Neoplasms; Female; Humans
PubMed: 33829532
DOI: 10.1111/his.14380 -
Surgical Pathology Clinics Mar 2021Epithelial-myoepithelial carcinoma is an uncommon low-grade salivary gland carcinoma. It is classically characterized by biphasic tubular structures composed of inner... (Review)
Review
Epithelial-myoepithelial carcinoma is an uncommon low-grade salivary gland carcinoma. It is classically characterized by biphasic tubular structures composed of inner eosinophilic ductal cells and outer clear myoepithelial cells. In addition, epithelial-myoepithelial carcinoma sometimes shows various histologic features, including a cribriform pattern, basaloid appearance, and sebaceous differentiation. Because clear myoepithelial cells are also noted in other benign and malignant salivary gland tumors, the histologic variety and similarity with other tumor entities make the diagnosis of epithelial-myoepithelial carcinoma challenging. A recent analysis revealed that HRAS hotspot point mutations are specifically identified in epithelial-myoepithelial carcinoma and the assessment of given genes facilitate the correct diagnosis.
Topics: Diagnosis, Differential; Epithelial Cells; Humans; Myoepithelioma; Point Mutation; Prognosis; Proto-Oncogene Proteins p21(ras); Salivary Gland Neoplasms
PubMed: 33526226
DOI: 10.1016/j.path.2020.10.002 -
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 -
Surgical Pathology Clinics Mar 2021Myoepithelial carcinoma (MECA) may overlap histologically with other salivary gland neoplasms, especially pleomorphic adenoma. MECA is characterized by cellular, uniform... (Review)
Review
Myoepithelial carcinoma (MECA) may overlap histologically with other salivary gland neoplasms, especially pleomorphic adenoma. MECA is characterized by cellular, uniform growth of myoepithelial cells and multinodular expansile invasive pattern with zonal cellular distribution. It may arise de novo or in association with pleomorphic adenoma (myoepithelial carcinoma ex pleomorphic adenoma). By immunohistochemistry, MECA is positive for cytokeratins and at least one of the myoepithelial markers, including S100. PLAG1 fusion is the most common genetic alteration. Carcinoma ex pleomorphic adenoma and necrosis correlate with worse clinical outcome in MECA, and necrosis can be used to stratify MECA as high grade.
Topics: Adenoma, Pleomorphic; Diagnosis, Differential; Epithelial Cells; Humans; Immunohistochemistry; Myoepithelioma; Necrosis; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Prognosis; Salivary Gland Neoplasms
PubMed: 33526224
DOI: 10.1016/j.path.2020.09.008 -
Cell Jan 2022Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor...
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.
Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Cell Differentiation; Cohort Studies; Disease Progression; Epithelial Cells; Epithelium; Extracellular Matrix; Female; Fibroblasts; Humans; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Phenotype; Single-Cell Analysis; Stromal Cells; Tumor Microenvironment
PubMed: 35063072
DOI: 10.1016/j.cell.2021.12.023 -
Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing.Cell Reports Dec 2020Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary...
Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary gland. Here, we leverage high-throughput single-cell RNA sequencing to generate a detailed transcriptomic atlas of young and aged murine mammary tissues. By analyzing epithelial, stromal, and immune cells, we identify age-dependent alterations in cell proportions and gene expression, providing evidence that suggests alveolar maturation and physiological decline. The analysis also uncovers potential pro-tumorigenic mechanisms coupled to the age-associated loss of tumor suppressor function and change in microenvironment. In addition, we identify a rare, age-dependent luminal population co-expressing hormone-sensing and secretory-alveolar lineage markers, as well as two macrophage populations expressing distinct gene signatures, underscoring the complex heterogeneity of the mammary epithelia and stroma. Collectively, this rich single-cell atlas reveals the effects of aging on mammary physiology and can serve as a useful resource for understanding aging-associated cancer risk.
Topics: Aging; Animals; Biomarkers; Cells, Cultured; Cellular Senescence; Dendritic Cells; Epithelial Cells; Female; Gene Expression Regulation; Genes, Tumor Suppressor; High-Throughput Nucleotide Sequencing; Lymphocytes; Macrophages; Mammary Glands, Animal; Mice, Inbred C57BL; Single-Cell Analysis; Stromal Cells; Transcriptome
PubMed: 33378681
DOI: 10.1016/j.celrep.2020.108566 -
Modern Pathology : An Official Journal... Jan 2021Papillary neoplasms of the breast are a heterogeneous group of epithelial tumors nearly entirely composed of papillae. Their classification rests on the characteristics... (Review)
Review
Papillary neoplasms of the breast are a heterogeneous group of epithelial tumors nearly entirely composed of papillae. Their classification rests on the characteristics of the epithelium and the presence and distribution of the myoepithelial cells along the papillae and around the tumor. Papillary neoplasms of the breast can be diagnostically challenging, especially if only core needle biopsy (CNB) material is available. This review summarizes salient morphological and immunohistochemical features, clinical presentation, and differential diagnoses of papillary neoplasms of the breast. We include a contemporary appraisal of the upgrade rate to carcinoma (invasive carcinoma and ductal carcinoma in situ [DCIS]) and atypical hyperplasias in surgical excision specimens obtained following CNB diagnosis of papilloma without atypia, and a review of the available follow-up data in cases without immediate surgical excision.
Topics: Biopsy, Large-Core Needle; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Diagnosis, Differential; Epithelial Cells; Female; Humans; Hyperplasia; Neoplasm Grading; Papilloma, Intraductal; Retrospective Studies
PubMed: 33106592
DOI: 10.1038/s41379-020-00706-5 -
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 -
Nature Communications Jun 2022Salivary glands that produce and secrete saliva, which is essential for lubrication, digestion, immunity, and oral homeostasis, consist of diverse cells. The long-term...
Salivary glands that produce and secrete saliva, which is essential for lubrication, digestion, immunity, and oral homeostasis, consist of diverse cells. The long-term maintenance of diverse salivary gland cells in organoids remains problematic. Here, we establish long-term murine and human salivary gland organoid cultures. Murine and human salivary gland organoids express gland-specific genes and proteins of acinar, myoepithelial, and duct cells, and exhibit gland functions when stimulated with neurotransmitters. Furthermore, human salivary gland organoids are established from isolated basal or luminal cells, retaining their characteristics. Single-cell RNA sequencing also indicates that human salivary gland organoids contain heterogeneous cell types and replicate glandular diversity. Our protocol also enables the generation of tumoroid cultures from benign and malignant salivary gland tumor types, in which tumor-specific gene signatures are well-conserved. In this study, we provide an experimental platform for the exploration of precision medicine in the era of tissue regeneration and anticancer treatment.
Topics: Animals; Humans; Mice; Organoids; Saliva; Salivary Gland Neoplasms; Salivary Glands
PubMed: 35672412
DOI: 10.1038/s41467-022-30934-z