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Cell Reports Nov 2022Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling...
Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors.
Topics: Humans; Carcinoma, Adenoid Cystic; Oncogenes; Carcinogenesis; Exome Sequencing; Sequence Analysis, RNA
PubMed: 36450256
DOI: 10.1016/j.celrep.2022.111743 -
Advances in Anatomic Pathology Jul 2022This review focuses on the heterogenous group of clear cell neoplasms of salivary glands and attempts to identify major differential diagnostic features. Within the head... (Review)
Review
This review focuses on the heterogenous group of clear cell neoplasms of salivary glands and attempts to identify major differential diagnostic features. Within the head and neck region, clear cells are found most commonly in salivary gland tumors, but may also be seen in tumors of squamous or odontogenic epithelial origin, primary or metastatic carcinomas, benign or malignant melanocytic lesions, or benign or malignant mesenchymal tumors. Clear cells occur fairly commonly among a wide variety of salivary gland neoplasms, but mostly they constitute only a minor component of the tumor cell population. Clear cells represent a major diagnostic feature in two salivary gland neoplasms, epithelial-myoepithelial carcinoma and hyalinizing clear cell carcinoma. In addition, salivary gland neoplasms composed predominantly of clear cells could also include clear cell variants of other salivary neoplasms, such as mucoepidermoid carcinoma and myoepithelial carcinoma, but their tumor type-specific histologic features may only be available in limited nonclear cell areas of the tumor. Diagnosing predominantly clear cell salivary gland tumors is difficult because the immunoprofiles and morphologic features may overlap and the same tumor entity may also have a wide range of other histologic presentations. Many salivary gland tumors are characterized by tumor type-specific genomic alterations, particularly gene fusions of the ETV6 gene in secretory carcinoma, the MYB and MYBL1 genes in adenoid cystic carcinoma, the MAML2 gene in mucoepidermoid carcinoma, the EWSR1 gene in hyalinizing clear cell carcinoma, and others. Thus, along with conventional histopathologic examination and immunoprofiling, molecular and genetic tests may be important in the diagnosis of salivary gland clear cell tumors by demonstrating genetic alterations specific to them.
Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Mucoepidermoid; Humans; Salivary Gland Neoplasms; Salivary Glands
PubMed: 35249992
DOI: 10.1097/PAP.0000000000000339 -
Cellular and Molecular Life Sciences :... Apr 2021The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian... (Review)
Review
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review focuses on research conducted on mammalian salivary gland development, particularly on the differentiation of acinar, ductal, and myoepithelial cells. We discuss recent studies that provide conceptual advances in the understanding of the molecular mechanisms of salivary gland development. In addition, we describe the organogenesis of submandibular glands (SMGs), model systems used for the study of SMG development, and the key signaling pathways as well as cellular processes involved in salivary gland development. The findings from the recent studies elucidating the identity of stem/progenitor cells in the SMGs, and the process by which they are directed along a series of cell fate decisions to form functional glands, are also discussed. Advances in genetic tools and tissue engineering strategies will significantly increase our knowledge about the mechanisms by which signaling pathways and cells establish tissue architecture and function during salivary gland development, which may also be conserved in the growth and development of other organ systems. An increased knowledge of organ development mechanisms will have profound implications in the design of therapies for the regrowth or repair of injured tissues. In addition, understanding how the processes of cell survival, expansion, specification, movement, and communication with neighboring cells are regulated under physiological and pathological conditions is critical to the development of future treatments.
Topics: Animals; Cell Differentiation; Humans; Organogenesis; Salivary Glands; Signal Transduction; Stem Cells
PubMed: 33449148
DOI: 10.1007/s00018-020-03741-2 -
Journal of Cancer 2023Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to , and to invasive and metastatic stages. Given that...
Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to , and to invasive and metastatic stages. Given that over 90% of cancer deaths are caused by invasive and metastatic lesions, countless factors and multiple theories have been proposed as the triggering factor for the cascade of actions of cancer invasion. However, those factors and theories are largely based on the studies of cell lines or animal models. In addition, corresponding interventions based on these factors and theories have failed to reduce the incidence rate of invasive and metastatic lesions, suggesting that previous efforts may have failed to arm at the right target. Considering these facts and observations, we are proposing "A focal aberrant degeneration in the myoepithelial cell layer (MECL) as the most likely triggering factor for breast cancer invasion". Our hypothesis is based on our recent studies of breast and multiple other cancers. Our commentary provides the rationale, morphologic, immunohistochemical, and molecular data to support our hypotheses. As all epithelium-derived cancers share a very similar architecture, our hypothesis is likely to be applicable to invasion of all cancer types. We believe that human tissue-derived data may provide a more realistic roadmap to guide the clinic practice.
PubMed: 37057291
DOI: 10.7150/jca.82291 -
Journal of the American Society of... 2022Eccrine spiradenoma (ES) is a rare benign cutaneous adnexal tumor. The aim of our study was to discuss the clinical presentation, cytomorphologic features, and...
INTRODUCTION
Eccrine spiradenoma (ES) is a rare benign cutaneous adnexal tumor. The aim of our study was to discuss the clinical presentation, cytomorphologic features, and differential diagnosis of a series of 3 cases of ES diagnosed by fine needle aspiration (FNA).
MATERIALS AND METHODS
The pathology databases were searched for cases of ES diagnosed by FNA and confirmed by follow-up surgical excision. FNA smears, cell blocks, and histologic sections were examined.
RESULTS
Three cases of ES that had presented as a soft tissue mass from 3 patients were reviewed. The sites included the left forearm, left leg, and left ankle. Cytology smears showed the presence of hypercellular 3-dimensional dense cell clusters and smaller loose cell aggregates, single cells, and bare nuclei. Most cells had round to oval nuclei, scant cytoplasm, and indistinct cell borders. A second population of cells had more spindled nuclei and were often dispersed as single cells. Scattered lymphocytes were present. Two cases showed the presence of pseudo-rosettes composed of hyaline globules of basement membrane-like material with a surrounding row of basaloid cells. None of the cases showed cytologic atypia, necrosis, or mitoses. Immunohistochemistry was used in 2 cases and showed positive staining with myoepithelial markers (smooth muscle actin, calponin, S100, and CK5). The cytology diagnoses were ES, basaloid cutaneous adnexal neoplasm, and suspicious for ES.
CONCLUSIONS
FNA cytopathology of ES demonstrated banal basaloid and spindle cells, lymphocytes, and infrequent metachromatic-stained hyaline globules. A specific diagnosis requires immunohistochemistry testing to avoid confusion with other cutaneous basaloid neoplasms.
Topics: Acrospiroma; Biopsy, Fine-Needle; Cytodiagnosis; Humans; Immunohistochemistry; Skin Neoplasms; Sweat Gland Neoplasms
PubMed: 35672250
DOI: 10.1016/j.jasc.2022.05.002 -
Biochimica Et Biophysica Acta.... Jan 2022Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known... (Review)
Review
Nearly all mammals rely on lactation to support their young and to ensure the continued survival of their species. Despite its importance, relatively little is known about how milk is produced and how it is ejected from the lumen of mammary alveoli and ducts. This review focuses on the latter. We discuss how a relatively small number of basal cells, wrapping around each alveolar unit, contract to forcibly expel milk from the alveolar lumen. We consider how individual basal cells coordinate their activity, the fate of these cells at the end of lactation and avenues for future deliberation and exploration.
Topics: Animals; Cell Plasticity; Epithelial Cells; Female; Humans; Lactation; Mammary Glands, Human
PubMed: 34653580
DOI: 10.1016/j.bbamcr.2021.119159 -
Journal of Inflammation Research 2023Adenomyosis (AM) is a common benign uterine disorder that has deleterious effects on women's health. However, the pathogenesis of AM is not clearly understood. We aimed...
PURPOSE
Adenomyosis (AM) is a common benign uterine disorder that has deleterious effects on women's health. However, the pathogenesis of AM is not clearly understood. We aimed to investigate the pathophysiological changes and molecular mechanism in AM.
METHODS
Single-cell RNA sequencing (scRNA-seq) was employed to construct a transcriptomic atlas of various cell subsets from the ectopic endometrium (EC) and eutopic endometrium (EM) of one AM patient and evaluate differential expression. The Cell Ranger software pipeline (version 4.0.0) was applied to conduct sample demultiplexing, barcode processing and mapping reads to the reference genome (human GRCh38). Different cell types were classified with markers with the "FindAllMarkers" function, and differential gene expression analysis was performed with Seurat software in R. The findings were confirmed by Reverse Transcription Real-Time PCR using samples from three AM patients.
RESULTS
We identified nine cell types: endothelial cells, epithelial cells, myoepithelial cells, smooth muscle cells, fibroblasts, lymphocytes, mast cells, macrophages and unknown cells. A number of differentially expressed genes, including and , were identified from all cell types. Functional enrichment showed that aberrant gene expression in fibroblasts and immune cells was related to fibrosis-associated terms, such as extracellular matrix dysregulation, focal adhesion and the PI3K-Akt signaling pathway. We also identified fibroblast subtypes and determined a potential developmental trajectory related to AM. In addition, we identified increased cell-cell communication patterns in EC, highlighting the imbalanced microenvironment in AM progression.
CONCLUSION
Our results support the theory of endometrial-myometrial interface disruption for AM, and repeated tissue injury and repair could lead to increased fibrosis in the endometrium. Therefore, the present study reveals the association between fibrosis, the microenvironment, and AM pathogenesis. This study provides insight into the molecular mechanisms regulating AM progression.
PubMed: 37179754
DOI: 10.2147/JIR.S402734 -
Journal of Dental Research Oct 2019Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune... (Review)
Review
Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren's syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.
Topics: Animals; Cell Lineage; Epithelial Cells; Keratins; Mice; SOX Transcription Factors; Salivary Glands; Signal Transduction; Trans-Activators
PubMed: 31331226
DOI: 10.1177/0022034519864592 -
The Journal of Cell Biology Aug 2019In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and... (Review)
Review
In epithelial cancers, cells must invade through basement membranes (BMs) to metastasize. The BM, a thin layer of extracellular matrix underlying epithelial and endothelial tissues, is primarily composed of laminin and collagen IV and serves as a structural barrier to cancer cell invasion, intravasation, and extravasation. BM invasion has been thought to require protease degradation since cells, which are typically on the order of 10 µm in size, are too large to squeeze through the nanometer-scale pores of the BM. However, recent studies point toward a more complex picture, with physical forces generated by cancer cells facilitating protease-independent BM invasion. Moreover, collective cell interactions, proliferation, cancer-associated fibroblasts, myoepithelial cells, and immune cells are all implicated in regulating BM invasion through physical forces. A comprehensive understanding of BM structure and mechanics and diverse modes of BM invasion may yield new strategies for blocking cancer progression and metastasis.
Topics: Animals; Basement Membrane; Biomechanical Phenomena; Cell Communication; Humans; Neoplasm Invasiveness; Neoplasms; Peptide Hydrolases
PubMed: 31315943
DOI: 10.1083/jcb.201903066