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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 -
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 -
Journal of Oncology 2022Pulmonary epithelial-myoepithelial carcinoma (P-EMC) is an exceptionally rare subtype of salivary gland lung tumor originating from tracheobronchial glands. P-EMC is a... (Review)
Review
Pulmonary epithelial-myoepithelial carcinoma (P-EMC) is an exceptionally rare subtype of salivary gland lung tumor originating from tracheobronchial glands. P-EMC is a biphasic tumor consisting of an inner layer of epithelial cells and an outer layer of spindle-shaped, clear-cell-like myoepithelial cells. Bronchial obstruction symptom is the main clinical characteristic for P-EMC. Because its clinical and imaging characteristics are highly similar to other types of non-small-cell lung cancer (NSCLC), it is easy to cause missed diagnosis and misdiagnosis. The diagnosis is mainly based on the pathology and immunohistochemistry with an inner layer of epithelial cells immunoreactive for cytokeratin and an outside layer of myoepithelial cells immunoreactive for S100 protein (S-100) and smooth muscle actin (SMA). Therefore, positive for cytokeratin, S-100 and SMA can assist in the diagnosis. Although in general, P-EMC is a low-grade malignant neoplasm, it may occasionally recur and metastasize. The optimal method for P-EMC treatment has not been established, and surgical resection is still the main clinical method. Radiotherapy and chemotherapy have been shown not sensitive for P-EMC treatment, whereas targeted therapy and immunotherapy have not evaluated in clinical practice. This review focuses on the pathological characteristics, molecular characteristics, diagnosis, treatment, and prognosis of P-EMC.
PubMed: 36268279
DOI: 10.1155/2022/4559550 -
Advances in Experimental Medicine and... 2019Epithelial stem cells reside within multiple regions of the lung where they renew various region-specific cells. In addition, there are multiple routes of regeneration... (Review)
Review
Epithelial stem cells reside within multiple regions of the lung where they renew various region-specific cells. In addition, there are multiple routes of regeneration after injury through built-in heterogeneity within stem cell populations and through a capacity for cellular plasticity among differentiated cells. These processes are important facets of respiratory tissue resiliency and organism survival. However, this regenerative capacity is not limitless, and repetitive or chronic injuries, environmental stresses, or underlying factors of disease may ultimately lead to or contribute to tissue remodeling and end-stage lung disease. This chapter will review stem cell heterogeneity among pulmonary epithelia in the lower respiratory system, discuss recent findings that may challenge long-held scientific paradigms, and identify several clinically relevant research opportunities for regenerative medicine.
Topics: Animals; Cell Differentiation; Humans; Lung; Stem Cells
PubMed: 31487021
DOI: 10.1007/978-3-030-24108-7_6 -
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 -
Journal of Pharmacy & Bioallied Sciences Aug 2015Myoepithelioma is a benign salivary gland tumor in the head and neck region, accounting for 1-1.5% of all glandular tumors. The diagnosis is rendered...
Myoepithelioma is a benign salivary gland tumor in the head and neck region, accounting for 1-1.5% of all glandular tumors. The diagnosis is rendered histopathologically, and it includes the proliferation of myoepithelial cells, without chondroid or myxochondroid stroma and ductal components (up to 5% of ductal component is acceptable). In our case report, this lesion has occurred in a 46-year-old female patient, and presented as well defined, nodular growth on the right posterior palatal region. Bony erosion and invasion were observed radiographically, and the lesion was excised surgically, with 1-2 cm of clear margin. The microscopic features included proliferating tumor sheets, composed of bland looking spindle and plasmacytoid shaped myoepithelial cells, and few cells showed clear cytoplasm, which were confirmed immunohistochemically as myoepithelial cells. Thus, the final diagnosis of benign myoepithelioma was rendered and no recurrence had been reported so far in the regular follow-up.
PubMed: 26538968
DOI: 10.4103/0975-7406.163560 -
PloS One 2022The salivary gland can be permanently impaired by radiation treatment for head and neck cancers. Efforts at tissue regeneration have focused on saliva-producing acinar...
The salivary gland can be permanently impaired by radiation treatment for head and neck cancers. Efforts at tissue regeneration have focused on saliva-producing acinar cells. However, myoepithelial cells are also critical to gland function, but mechanisms that regulate their differentiation are poorly defined. To study myoepithelial differentiation, we employed mSG-PAC1 murine salivary gland epithelial cells. We demonstrate that mSG-PAC1 spheroids exhibit phenotypic plasticity between pro-acinar and myoepithelial cell fates. Increased expression of pro-acinar/acinar or myoepithelial RNAs was identified from spheroids cultured under different media conditions by microarray followed by gene-set enrichment analysis. Spheroids cultured with different medium components expressed proteins typical of either acinar or myoepithelial cells, as detected by immunocytochemistry. We demonstrate that the pattern of TAZ expression in the epithelial compartment of the differentiating murine salivary gland correlates with the expression of the myoepithelial marker alpha-SMA, as is the case for TAZ expression in mSG-PAC1 spheroids. Our analysis also indicates that YAP/TAZ target genes are upregulated together with myoepithelial markers. Importantly, siRNA targeting of TAZ expression in mSG-PAC1 spheroids diminished the expression of myoepithelial markers. Our results in this in vitro cell model implicate TAZ signaling in myoepithelial differentiation.
Topics: Animals; Mice; Acinar Cells; Cell Differentiation; Epithelial Cells; Salivary Glands
PubMed: 35617216
DOI: 10.1371/journal.pone.0268668