-
Matrix Biology : Journal of the... Aug 2023Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply...
Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply degraders of the matrix, but also play fundamental roles in modulating cellular behaviour through the proteolytic processing of specific substrates. Indeed, proteases can elicit both pro- and anti- tumorigenic effects depending on context. Using a heterocellular spheroid model of breast cancer progression, we demonstrate the repressive function of myoepithelial ADAMTS3, with its loss directing myoepithelial-led invasion of luminal cells through a physiologically relevant matrix. Degradomic analysis, using terminal amine isotopic labelling of substrates (TAILS), combined with functional assays, implicate ADAMTS3 as a mediator of fibronectin degradation. We show further that loss of ADAMTS3 enhances levels of fibronectin in the microenvironment, promoting invasion through canonical integrin α5β1 activation. Our data highlight a tumour suppressive role for ADAMTS3 in early stage breast cancer, and contribute to the growing evidence that proteases can restrain cancer progression.
Topics: Female; Humans; Breast; Breast Neoplasms; Cell Line, Tumor; Fibronectins; Peptide Hydrolases; Tumor Microenvironment
PubMed: 37336268
DOI: 10.1016/j.matbio.2023.06.005 -
Translational Oncology Sep 2023Active breast cancer-associated fibroblasts (CAFs) promote tumor growth and spread, and like tumor cells they are also heterogeneous with various molecular sub-types and...
BACKGROUND
Active breast cancer-associated fibroblasts (CAFs) promote tumor growth and spread, and like tumor cells they are also heterogeneous with various molecular sub-types and different pro-tumorigenic capacities.
METHODS
We have used immunoblotting as well as quantitative RT-PCR to assess the expression of various epithelial/mesenchymal as well as stemness markers in breast stromal fibroblasts. Immunofluorescence was utilized to assess the level of different myoepithelial and luminal markers at the cellular level. Flow cytometry allowed to determine the proportion of CD44- and ALDH1-positive breast fibroblasts, while sphere formation assay was used to test the ability of these cells to form mammospheres.
RESULTS
We have shown here that IL-6-dependent activation of breast and skin fibroblasts promotes mesenchymal-to-epithelial transition and stemness in a STAT3- and p16-dependent manner. Interestingly, most primary CAFs isolated from breast cancer patients exhibited such transition and expressed lower levels of the mesenchymal markers N-cadherin and vimentin as compared to their adjacent normal fibroblasts (TCFs) isolated from the same patients. We have also shown that some CAFs and IL-6-activated fibroblasts express high levels of the myoepithelial markers cytokeratin 14 and CD10. Interestingly, 12 CAFs isolated from breast tumors showed higher proportions of CD24/CD44 and ALDH cells, compared to their corresponding TCF cells. These CD44 cells have higher abilities to form mammospheres and to enhance cell proliferation of breast cancer cells in a paracrine manner relative to their corresponding CD44 cells.
CONCLUSION
Together, the present findings show novel characteristics of active breast stromal fibroblasts, which exhibit additional myoepithelial/progenitor features.
PubMed: 37329829
DOI: 10.1016/j.tranon.2023.101721 -
Head and Neck Pathology Feb 2024Pleomorphic adenoma is a well-known benign salivary gland neoplasm characterized by the presence of varying proportions of three different components, including... (Review)
Review
BACKGROUND
Pleomorphic adenoma is a well-known benign salivary gland neoplasm characterized by the presence of varying proportions of three different components, including bi-layered ducts, myoepithelial cells, and admixed within a chondromyxoid/fibrous stroma.
METHOD
We report an interesting case of an adult male who presented with bleeding from an extensively degenerated parotid gland mass, concerning for a vascular neoplasm versus primary malignant tumor. Microscopically, majority of the viable tumor exhibited diffuse proliferation of spindle to epithelioid cells, with focal areas depicting cribriform glands, ducts, and scant chondromyxoid stroma.
RESULT
Next-generation sequencing (NGS) RNA-based fusion panel analysis identified a gene rearrangement involving the pleomorphic adenoma gene 1 (PLAG1), with a novel, cryptogenic fusion partner known as LINC01606; [LINC01606::PLAG1; inv(8;8)(8q12.1;8q12.1)].
CONCLUSION
To the best of our knowledge, this is the first documented case of a long non-coding RNA (lnc-RNA) serving as a rearrangement partner with the PLAG1 gene. We reviewed the molecular characteristics of this entity and explored the potential role of LINC01606::PLAG1 in the tumorigenesis of pleomorphic adenoma.
Topics: Adult; Male; Humans; Adenoma, Pleomorphic; DNA-Binding Proteins; Salivary Gland Neoplasms; Gene Rearrangement; RNA
PubMed: 38393488
DOI: 10.1007/s12105-024-01612-x -
Cytopathology : Official Journal of the... Mar 2024The co-existence of granulomatous mastitis and collagenous spherulosis in a breast lump is an uncommon finding. The awareness of cytomorphological features can help...
The co-existence of granulomatous mastitis and collagenous spherulosis in a breast lump is an uncommon finding. The awareness of cytomorphological features can help corroborate a cytological diagnosis. A palpable breast lump in an elderly female warrants urgent attention and fine needle aspiration is a rapid, reliable method of evaluation. An elderly female with a firm breast lump mimicking malignancy was subjected to fine needle aspiration cytology (FNAC). Smears showed ill-formed granulomas, inflammatory cells and homogeneous hyaline stromal globular elements intermingled with the benign ductal epithelial and myoepithelial cells.
Topics: Female; Humans; Aged; Breast; Breast Neoplasms; Biopsy, Fine-Needle; Epithelial Cells; Hyperplasia
PubMed: 37874012
DOI: 10.1111/cyt.13316 -
Research Square Apr 2024Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells...
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low level expression of the Wnt target gene . Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and expression and promotes their Taz mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.
PubMed: 38746309
DOI: 10.21203/rs.3.rs-4177351/v1 -
Research Square May 2024Ductal carcinoma (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent...
Ductal carcinoma (DCIS) constitutes an array of morphologically recognized intraductal neoplasms in the mammary ductal tree defined by an increased risk for subsequent invasive carcinomas at or near the site of biopsy detection. However, only 15-45% of untreated DCIS cases progress to invasive cancer, so understanding mechanisms that prevent progression is key to avoid overtreatment and provides a basis for alternative therapies and prevention. This study was designed to characterize the tumor microenvironment and molecular profile of high-risk DCIS that grew to a large size but remained as DCIS. All patients had DCIS lesions >5cm in size with at least one additional high-risk feature: young age (<45 years), high nuclear grade, hormone receptor negativity, HER2 positivity, the presence of comedonecrosis, or a palpable mass. The tumor immune microenvironment was characterized using multiplex immunofluorescence to identify immune cells and their spatial relationships within the ducts and stroma. Gene copy number analysis and whole exome DNA sequencing identified the mutational burden and driver mutations, and quantitative whole-transcriptome/gene expression analyses were performed. There was no association between the percent of the DCIS genome characterized by copy number variants (CNAs) and recurrence events (DCIS or invasive). Mutations, especially missense mutations, in the breast cancer driver genes and were common in this high-risk DCIS cohort (47% of evaluated lesions). Tumor infiltrating lymphocyte (TIL) density was higher in DCIS lesions with TP53 mutations (p=0.0079) compared to wildtype lesions, but not in lesions with mutations (p=0.44). Immune infiltrates were negatively associated with hormone receptor status and positively associated with HER2 expression. High levels of CD3+CD8- T cells were associated with good outcomes with respect to any subsequent recurrence (DCIS or invasive cancer), whereas high levels of CD3+Foxp3+ Treg cells were associated with poor outcomes. Spatial proximity analyses of immune cells and tumor cells demonstrated that close proximity of T cells with tumor cells was associated with good outcomes with respect to any recurrence as well as invasive recurrences. Interestingly, we found that myoepithelial continuity (distance between myoepithelial cells surrounding the involved ducts) was significantly lower in DCIS lesions compared to normal tissue (p=0.0002) or to atypical ductal hyperplasia (p=0.011). Gene set enrichment analysis identified several immune pathways associated with low myoepithelial continuity and a low myoepithelial continuity score was associated with better outcomes, suggesting that gaps in the myoepithelial layer may allow access/interactions between immune infiltrates and tumor cells. Our study demonstrates the immune microenvironment of DCIS, in particular the spatial proximity of tumor cells and T cells, and myoepithelial continuity are important determinants for progression of disease.
PubMed: 38766192
DOI: 10.21203/rs.3.rs-4126092/v1 -
Japanese Journal of Clinical Oncology Mar 2024Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their... (Review)
Review
Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes.
Topics: Humans; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Salivary Gland Neoplasms; Carcinoma; Myoepithelioma; Salivary Glands; Lung Neoplasms
PubMed: 38018262
DOI: 10.1093/jjco/hyad160 -
The Journal of Allergy and Clinical... Jan 2024Little is known about nasal epithelial gene expression and total IgE in youth.
BACKGROUND
Little is known about nasal epithelial gene expression and total IgE in youth.
OBJECTIVE
We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types.
METHODS
We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma. We then attempted to replicate top findings for each analysis using data from 3 cohorts. Genes with a Benjamini-Hochberg-adjusted P value of less than .05 in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study and a P value of less than .05 in the same direction of association in 1 or more replication cohort were considered differentially expressed genes (DEGs). DEGs for total IgE in subjects with asthma were further dissected into gene modules using coexpression analysis, and such modules were mapped to specific cell types in airway epithelia using public single-cell RNA-sequencing data.
RESULTS
A higher number of DEGs for total IgE were identified in subjects with asthma (n = 1179 DEGs) than in all subjects (n = 631 DEGs). In subjects with asthma, DEGs were mapped to 11 gene modules. The top module for positive correlation with total IgE was mapped to myoepithelial and mucus secretory cells in lower airway epithelia and was regulated by IL-4, IL5, IL-13, and IL-33. Within this module, hub genes included CDH26, FETUB, NTRK2, CCBL1, CST1, and CST2. Furthermore, an enrichment analysis showed overrepresentation of genes in signaling pathways for synaptogenesis, IL-13, and ferroptosis, supporting interactions between interleukin- and acetylcholine-induced responses.
CONCLUSIONS
Our findings for nasal epithelial gene expression support neuroimmune coregulation of total IgE in youth with asthma.
Topics: Child; Humans; Adolescent; Interleukin-13; Asthma; Nose; Transcriptome; Immunoglobulin E
PubMed: 37742934
DOI: 10.1016/j.jaci.2023.09.014 -
Nature Communications Oct 2023Exocrine acinar cells in salivary glands (SG) are critical for oral health and loss of functional acinar cells is a major clinical challenge. Fibroblast growth factor...
Exocrine acinar cells in salivary glands (SG) are critical for oral health and loss of functional acinar cells is a major clinical challenge. Fibroblast growth factor receptors (FGFR) are essential for early development of multiple organs, including SG. However, the role of FGFR signaling in specific populations later in development and during acinar differentiation are unknown. Here, we use scRNAseq and conditional deletion of murine FGFRs in vivo to identify essential roles for FGFRs in craniofacial, early SG development and progenitor function during duct homeostasis. Importantly, we also discover that FGFR2 via MAPK signaling is critical for seromucous acinar differentiation and secretory gene expression, while FGFR1 is dispensable. We show that FGF7, expressed by myoepithelial cells (MEC), activates the FGFR2-dependent seromucous transcriptional program. Here, we propose a model where MEC-derived FGF7 drives seromucous acinar differentiation, providing a rationale for targeting FGFR2 signaling in regenerative therapies to restore acinar function.
Topics: Animals; Mice; Cell Differentiation; Homeostasis; Orosomucoid; Salivary Glands; Signal Transduction
PubMed: 37838739
DOI: 10.1038/s41467-023-42243-0 -
Reproduction and Breeding Sep 2023The human mammary gland is the major organ involved in lactation. In the mammary gland, alveoli secrete milk and myoepithelial cells contract to propel the milk through...
The human mammary gland is the major organ involved in lactation. In the mammary gland, alveoli secrete milk and myoepithelial cells contract to propel the milk through branched structures called ducts and eventually to the nipple. It is through this process of lactation that infants receive milk, which is essential for proper infant growth and development. The lactation process is comprised of sophisticated interactive networks at the cellular level that are not well understood. Whereas the majority of published mammary gland lactation studies have relied on mouse mammary glands, recent advancements in techniques to study mammary glands enable reproduction of lactation using human-representative frameworks. Currently, the 3D breast organoid is the state-of-the-art model in human mammary gland research, utilizing induced pluripotent stem cells (iPSCs) or processed patient-derived breast tissues embedded in a special matrix that are then able to grow into complex structures that recapitulate aspects of native human breast tissue. Gaining comprehensive biological insight into the process of lactation through these breast tissue-mimetic 3D models is essential for further studies on lactation-associated human mammary gland diseases, human milk composition, and potential solutions to challenges in maternal milk accessibility. In this short review, the benefits and potential utility of 3D breast organoids in understanding the underlying science of lactation and advancing further human mammary gland studies are discussed.
PubMed: 37691768
DOI: 10.1016/j.repbre.2023.08.003