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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 -
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 -
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 -
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 -
The International Journal of... 2011Over the last few years, the discovery of basal-type mammary carcinomas and the association of the regenerative potential of the mammary epithelium with the basal... (Review)
Review
Over the last few years, the discovery of basal-type mammary carcinomas and the association of the regenerative potential of the mammary epithelium with the basal myoepithelial cell population have attracted considerable attention to this second major mammary lineage. However, many questions concerning the role of basal myoepithelial cells in mammary morphogenesis, functional differentiation and disease remain unanswered. Here, we discuss the mechanisms that control the myoepithelial cell differentiation essential for their contractile function, summarize new data concerning the roles played by cell-extracellular matrix (ECM), intercellular and paracrine interactions in the regulation of various aspects of the mammary basal myoepithelial cell functional activity. Finally, we analyze the contribution of the basal myoepithelial cells to the regenerative potential of the mammary epithelium and tumorigenesis.
Topics: Animals; Breast; Breast Neoplasms; Cell Communication; Cell Differentiation; Epithelial Cells; Extracellular Matrix; Female; Humans; Mammary Glands, Animal; Mice; Myoepithelioma; Paracrine Communication; Signal Transduction; Stem Cells
PubMed: 21948739
DOI: 10.1387/ijdb.113385mm -
The International Journal of... 2011Endothelial cells, which are the main agents of the angiogenic process in vertebrates, are lacking in the vessels of invertebrates. These are limited by the basement... (Review)
Review
Endothelial cells, which are the main agents of the angiogenic process in vertebrates, are lacking in the vessels of invertebrates. These are limited by the basement membranes of epithelial or myoepithelial cells. This fact leads to the questions of how vessels grow in invertebrates and how vertebrate angiogenesis evolved. We herein review the knowledge available about vascular growth in invertebrates. The cases described include the ascidian Botryllus, the annelid Hirudo and the squid Idiosepius. All these processes of vascular growth in invertebrates show substantial differences with the vertebrate angiogenesis, although the signalling system mediated by VEGF and its receptor VEGFR seems to be involved in all cases. However, VEGF signalling is used by many processes of cell directional migration, and it cannot be considered as a hallmark of angiogenesis. We also describe the close similarity between the molecular control of the endothelial angiogenesis and the branching morphogenesis of the tracheal system of insects. In both cases, the process is regulated by hypoxia and activates a leading tip cell which inhibits responsiveness of the adjacent cells through a Delta/Notch signalling pathway. We suggest that endothelial angiogenesis in vertebrates arose through cooption of this hypoxia-sensing mechanism by replacing the FGF/FGFR axis of insects by a VEGF/VEGFR-mediated system, and adding a second layer of control of the endothelial state (quiescent or activated) mediated by angiopoietins and Tie receptors. This evolutionarily new control mechanism of endothelial angiogenesis establishes an endothelial/perivascular cell crosstalking which does not exist in invertebrates.
Topics: Animals; Biological Evolution; Blood Vessels; Drosophila; Endothelial Cells; Invertebrates; Models, Biological; Neovascularization, Physiologic; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Vascular Endothelial Growth Factor A; Vertebrates
PubMed: 21732276
DOI: 10.1387/ijdb.103212rm -
WormBook : the Online Review of C.... Jan 2006Selective cell fusion is a natural part of development. It is found in sexually reproducing organisms that require fertilization to propagate and in muscles, placenta,... (Review)
Review
Selective cell fusion is a natural part of development. It is found in sexually reproducing organisms that require fertilization to propagate and in muscles, placenta, bones, lens of the eye and stem cells. Cell fusion is particularly important in the development of C. elegans: in addition to 300 sperm and oocytes that fuse during fertilization, 300 of the 1090 somatic cells born, fuse throughout development. Studies of cell fusion in C. elegans have shown that although different types of cells fuse, cell membrane merger is initiated through a common mechanism involving the action of one gene, eff-1. In worms with mutations that inactivate eff-1, almost none of the 300 somatic cells that normally fuse do so, but appear to differentiate, attach and behave in the same way as fusing cells. Such worms develop and survive but have numerous morphological, behavioral and fertility defects associated to cell fusion failure in the epidermis, pharynx, male tail, vulva and uterus. Cell fusion in embryonic dorsal epithelial cells has been analyzed in great detail by confocal microscopy using membrane fluorescent probes, apical junction markers and cytoplasmic aqueous fluorescent probes allowing the direct observation of membrane disappearance, pore expansion and cytoplasmic content mixing. The complete elimination of the membranes between two fusing cells takes about 30 min and involves vesiculation of the fusing membranes. Genetic and cell biological evidence indicates that eff-1 activity is both necessary and sufficient to fuse epithelial and myoepithelial cells in vivo. Based on electron microscopic analyses of intermediates of cell fusion in eff-1 mutants, it appears that eff-1 is required for both initiation and expansion of fusion pores, similar to the fusogen of Influenza virus. While only one gene encoding a novel candidate component of the cell membrane fusion machinery has been found, the nematode's cell fusion program is under the control of many cell-specific transcriptional regulators. A large number of these conserved regulators prevent cell fusion by repressing eff-1 activity. For example, if either ceh-16/engrailed or the GATA factor EGL-18/ELT-5 is inactivated, the lateral epidermal cells that normally do not fuse in the embryo will fuse causing embryonic lethality. And if either the Hox protein lin-39/Deformed or its cofactor ceh-20/Extradenticle is inactivated, the ventral epidermal vulval precursor cells that normally do not fuse in the larvae will fuse and the hermaphrodite will have no vulva. In addition, there is evidence for coordinated and complex regulation of lin-39 in the ventral epidermis by Ras, Wnt, Rb/E2F, NuRD and lin-15 pathways. It appears that in many cells that normally do not fuse, specific transcription complexes repress eff-1 expression preventing cell fusion. ref-2 (REgulator of Fusion-2) encodes a Zn-finger protein that is required to generate ventral Pn.p cells and to keep them unfused both in males and hermaphrodites. ref-2 is necessary, but not sufficient, to maintain Pn.p cells unfused. This review shows that far from cell fusion being an unusual phenomenon, there is the clear prospect that animal cells in all tissues are intrinsically programmed to fuse, and are only prevented from fusing by transcriptional and post-transcriptional control mechanisms. There are three major questions that remain open for future research: (1) How does eff-1 fuse cells? (2) How do Ras, Wnt, Rb, NuRD, E2F, heterochronic and other pathways control cell fusion? (3) What are the implications of cell fusion beyond worms?
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Fusion; Cell Membrane; Giant Cells; Humans; Membrane Fusion; Membrane Glycoproteins
PubMed: 18050486
DOI: 10.1895/wormbook.1.52.1