Membrane Mucin Research Articles

TRPV4 activation in human corneal epithelial cells promotes membrane mucin production

Given that the corneal epithelium is situated on the outermost part of the eye, its functions can be influenced by external temperatures and chemical substances. This study aimed to elucidate the expression profile of chemosensory receptors in corneal epithelial cells and analyze their role in eye function regulation. A comprehensive analysis of 425 chemosensory receptors in human corneal epithelial cells-transformed (HCE-T) revealed the functional expression of TRPV4. The activation of TRPV4 in HCE-T cells significantly increased the expression of membrane-associated mucins MUC1, MUC4, and MUC16, which are crucial for stabilizing tear films, with efficacy comparable to the active components of dry eye medications. The present study suggests that TRPV4, which is activated by body temperature, regulates mucin expression and proposes it as a novel target for dry eye treatment.

Discovery of a MUC3B gene reconstructs the membrane mucin gene cluster on human chromosome 7.

Human tissue surfaces are coated with mucins, a family of macromolecular sugar-laden proteins serving diverse functions from lubrication to the formation of selective biochemical barriers against harmful microorganisms and molecules. Membrane mucins are a distinct group of mucins that are attached to epithelial cell surfaces where they create a dense glycocalyx facing the extracellular environment. All mucin proteins carry long stretches of tandemly repeated sequences that undergo extensive O-linked glycosylation to form linear mucin domains. However, the repetitive nature of mucin domains makes them prone to recombination and renders their genetic sequences particularly difficult to read with standard sequencing technologies. As a result, human mucin genes suffer from significant sequence gaps that have hampered the investigation of gene function in health and disease. Here we leveraged a recent human genome assembly to characterize a previously unmapped MUC3B gene located at the q22 locus on chromosome 7, within a cluster of four structurally related membrane mucin genes that we name the MUC3 cluster. We found that MUC3B shares high sequence identity with the known MUC3A gene and that the two genes are governed by evolutionarily conserved regulatory elements. Furthermore, we show that MUC3A, MUC3B, MUC12, and MUC17 in the human MUC3 cluster are expressed in intestinal epithelial cells (IECs). Our results complete existing genetic gaps in the MUC3 cluster which is a conserved genetic unit in vertebrates. We anticipate our results to be the starting point for the detection of disease-associated polymorphisms in the human MUC3 cluster. Moreover, our study provides the basis for the exploration of intestinal mucin gene function in widely used experimental models such as human intestinal organoids and genetic mouse models.

The role of membrane mucin MUC4 in breast cancer metastasis.

A major barrier to the emergence of distant metastases is the survival of circulating tumor cells (CTCs) within the vasculature. Lethal stressors, including shear forces from blood flow, anoikis arising from cellular detachment, and exposure to natural killer cells, combine to subvert the ability of primary tumor cells to survive and ultimately seed distant lesions. Further attenuation of this rate-limiting process via therapeutic intervention offers a very attractive opportunity for improving cancer patient outcomes, in turn prompting the need for a deeper understanding of the molecular and cellular mechanisms underlying CTC viability. MUC4 is a very large and heavily glycosylated protein expressed at the apical surfaces of the epithelia of a variety of tissues, is involved in cellular growth signaling and adhesiveness, and contributes to the protection and lubrication of cellular linings. Analysis of patient-matched breast tumor specimens has demonstrated that MUC4 protein levels are upregulated in metastatic lesions relative to primary tumor among all breast tumor subtypes, pointing to a possible selective advantage for MUC4 overexpression in metastasis. Analysis of a genetically engineered mouse model of HER2-positive breast cancer has demonstrated that metastatic efficiency is markedly suppressed with Muc4 deletion and Muc4-knockout tumor cells are poorly associated with platelets and white blood cells known to support CTC viability. In this review, we discuss the diverse roles of MUC4 in tumor progression and metastasis and propose that intervening in MUC4 intercellular interactions with binding partners on blood-borne aggregating cells could potentially thwart breast cancer metastatic efficiency.

Role of membrane mucin MUC17 in enterocytic barrier dysfunction associated with Crohn’s disease

Abstract The aim of this study is to determine the role of membrane mucin MUC17 in Crohn’s disease (CD). The incidence of CD is increasing in Western countries. However, the epithelial defects that cause disease are unclear. CD is characterized by the disruption of intestinal barriers leading to detrimental bacterial challenges that result in chronic intestinal inflammation. Our recent studies show that enterocytes are coated by the membrane mucin MUC17 that creates a glycocalyx barrier that protects enterocytes against luminal bacteria (Layunta et al. 2021 Accepted). Despite recent advances in defining intestinal barriers, the role of MUC17 and glycocalyx in CD remains unknown. In order to determine the role of MUC17 and glycocalyx in CD, we studied MUC17 and glycocalyx in ileum biopsies from CD (n=10) and non-CD (n=29) patients collected at Sahlgrenska University Hospital (Gothenburg). Our preliminary data show that MUC17 is downregulated in CD. In mouse ileum, MUC17 forms the glycocalyx barrier. Then, we asked if decrement of MUC17 levels could affect glycocalyx barrier function in CD. To address this question we designed a glycocalyx permeability assay in which we can measure the barrier function of MUC17 in glycocalyx by incubating patient biopsies with live GFP-expression E.coli (GFP+ E.Coli) and exogenous molecules such as fluorescent dextran. Our results showed that the glycocalyx in ileum of CD patients was more penetrable to GFP+ E.Coli and dextran compared to non-CD patients. In summary, we propose that changes in MUC17 levels in the glycocalyx contributes to disruption of epithelial barrier function during CD. In addition, our novel glycocalyx permeability assay can be used to diagnose CD, and to evaluate treatment response in patients.

IL-22 promotes the formation of a MUC17 glycocalyx barrier in the postnatal small intestine during weaning

The intestine is under constant exposure to chemicals, antigens, and microorganisms from the external environment. Apical aspects of transporting epithelial cells (enterocytes) form a brush-border membrane (BBM), shaped by packed microvilli coated with a dense glycocalyx. We present evidence showing that the glycocalyx forms an epithelial barrier that prevents exogenous molecules and live bacteria from gaining access to BBM. We use a multi-omics approach to investigate the function and regulation of membrane mucins exposed on the BBM during postnatal development of the mouse small intestine. Muc17 is identified as a major membrane mucin in the glycocalyx that is specifically upregulated by IL-22 as part of an epithelial defense repertoire during weaning. High levels of IL-22 at time of weaning reprogram neonatal postmitotic progenitor enterocytes to differentiate into Muc17-expressing enterocytes, as found in the adult intestine during homeostasis. Our findings propose a role for Muc17 in epithelial barrier function in the small intestine.

The membrane mucin Msb2 regulates aflatoxin biosynthesis and pathogenicity in fungus Aspergillus flavus.

As a pathogenic fungus, Aspergillus flavus can produce carcinogenic aflatoxins (AFs), which poses a great threat to crops and animals. Msb2, the signalling mucin protein, is a part of mitogen-activated protein kinase (MAPK) pathway which contributes to a range of physiological processes. In this study, the roles of membrane mucin Msb2 were explored in A. flavus by the application of gene disruption. The deletion of msb2 gene (Δmsb2) caused defects in vegetative growth, sporulation and sclerotia formation when compared to WT and complement strain (Δmsb2C ) in A. flavus. Using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analysis, it was found that deletion of msb2 down-regulated aflatoxin B1 (AFB1 ) synthesis and decreased the infection capacity of A. flavus. Consistently, Msb2 responds to cell wall stress and osmotic stress by positively regulating the phosphorylation of MAP kinase. Notably, Δmsb2 mutant exhibited cell wall defect, and it was more sensitive to inhibitor caspofungin when compared to WT and Δmsb2C . Taking together, these results revealed that Msb2 plays key roles in morphological development process, stresses adaptation, secondary metabolism and pathogenicity in fungus A. flavus.

The High Osmolarity Glycerol (HOG) Pathway Functions in Osmosensing, Trap Morphogenesis and Conidiation of the Nematode-Trapping Fungus Arthrobotrys oligospora.

Hog1, a mitogen-activated protein kinase (MAPK), has been identified in diverse fungal species, and it regulates various cellular processes, such as osmoadaptation, nutrient-sensing, and pathogenesis. However, the roles that Hog1 plays in nematode-trapping fungi were previously unclear. Here, we characterized orthologs of Saccharomyces cerevisiae Hog1 and membrane mucin Msb2 in the nematode-trapping fungus Arthrobotrys oligospora. We generated gene deletion mutants of HOG1 and MSB2 in A. oligospora, and characterized their roles in osmosensing, growth, and trap morphogenesis. We found that both hog1 and msb2 mutants were highly sensitive to high osmolarity. Predation analyses further revealed that hog1 and msb2 deletion caused a reduction in trap formation and predation efficiency. Furthermore, HOG1 is required for conidiation in A. oligospora, demonstrating its critical role in this developmental pathway. In summary, this study demonstrated that the conserved Hog1 and Msb2 govern physiology, growth and development in the nematode-trapping fungus A. oligospora.

Membrane mucins of the intestine at a glance.

Membrane mucins cover most mucosal surfaces throughout the human body. The intestine harbors complex population of microorganisms (the microbiota) and numerous exogenous molecules that can harm the epithelium. In the colon, where the microbial burden is high, a mucus barrier forms the first line of defense by keeping bacteria away from the epithelial cells. In the small intestine where the mucus layer is less organized, microbes are kept at bay by peristalsis and antimicrobial peptides. Additionally, a dense glycocalyx consisting of extended and heavily glycosylated membrane mucins covers the surface of enterocytes. Whereas many aspects of mucosal barriers are being discovered, the function of membrane mucins remains a largely overlooked topic, mainly because we lack the necessary reagents and experimental animal models to investigate these large glycoproteins. In this Cell Science at a Glance article and accompanying poster, we highlight central concepts of membrane mucin biology and the role of membrane mucins as integral components of intestinal mucosal barriers. We also present the current consensus concerning the role of membrane mucins in host-microbe interactions. Moreover, we discuss how regulatory circuits that govern membrane mucins in the healthy gut display strong overlap with pathways that are perturbed during chronic inflammation. Finally, we review how dysregulation of intestinal membrane mucins may contribute to human diseases, such as inflammation and cancer.

P067 Advancing IL-22-Based Therapies for Inflammatory Bowel Diseases With Human Intestinal Organoids

BACKGROUND: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastro-intestinal tract for which the key elements in disease initiation and perpetuation are defects in epithelial barrier integrity and repair. Inducing and maintaining mucosal healing has the potential to address unmet medical need in IBD of achieving greater efficacy and more durable disease remission than current therapies. Recent studies suggest that IL-22 regulates epithelial homeostasis and promotes repair of epithelial damage, thus making IL-22 a promising target for IBD therapy. In an effort to better understand IL-22 biology we have used human colon organoids to strengthen our understanding of the mechanisms by which IL-22 regulates mucosal healing. METHODS: Human colon organoids derived from healthy and ulcerative colitis (UC) donor biopsies were cultured using a standard protocol and treated with recombinant IL-22 protein alone or in combination with microbial-derived metabolites at multiple concentrations and time points. Cell viability, organoid forming capacity, epithelial cell function, as well as gene expression analysis of markers of epithelial cell types and signaling pathways were then assessed. To recapitulate the inflammatory environments associated with IBD, organoids were also co-cultured with anti-CD3/CD28 activated T cells. In-vivo studies were also performed in naïve mice dosed with IL-22-Fc to evaluate the in-vitro/in-vivo translatability. RESULTS: IL-22 treatment led to stem cell survival, cell proliferation and production of anti-microbial peptides in organoids. IL-22 treatment also altered the mucus barrier by inducing an increase in membrane mucus but a decrease in both secreted mucus and goblet cell number. Interestingly, most of the IL-22 effects on the organoids were also observed in-vivo thus confirming the in vitro/in vivo translatability. In addition, IL-22 had the same inducing effect on anti-microbial peptides and the membrane mucus barrier in both healthy (n = 3) and UC (n = 3) organoids. In contrast, this IL-22-associated epithelial phenotype was different when organoids were co-cultured with activated T cells. Finally, IL-22 showed synergistic and additive effects with microbial-derived metabolites in inducing expression of antimicrobial peptides and membrane mucins. CONCLUSION(S): Our data indicate that IL-22 acts directly on the gut epithelium of both healthy and UC individuals to promote epithelial regeneration, innate defense and production of membrane mucus. In addition, our findings indicate that these IL-22 effects on epithelial cell function and mucosal healing mechanisms are differentially regulated in presence of either microbial-derived metabolites or activated T cells. Overall, this data strongly supports clinical relevance of IL-22 as a mucosal healing therapy in IBD and suggests that the efficacy may be impacted by microbial-derived metabolites and inflammatory environments.

MUC4-ErbB2 Oncogenic Complex: Binding studies using Microscale Thermophoresis

The MUC4 membrane-bound mucin is a large O-glycoprotein involved in epithelial homeostasis. At the cancer cell surface MUC4 interacts with ErbB2 receptor via EGF domains to promote cell proliferation and migration. MUC4 is highly regarded as a therapeutic target in pancreatic cancer as it is not expressed in healthy pancreas, while it is neoexpressed in early preneoplastic stages (PanINs). However, the association/dissociation constant of MUC4-ErbB2 complex is unknown. Protein-protein interactions (PPIs) have become a major area of research in the past years and the characterization of their interactions, especially by biophysical methods, is intensively used in drug discovery. To characterize the MUC4-ErbB2 interaction, we used MicroScale Thermophoresis (MST), a powerful method for quantitative protein interaction analysis under challenging conditions. We worked with CHO cell lysates containing either the transmembrane β subunit of MUC4 (MUC4β) or a truncated mutant encompassing only the EGF domains (MUC4EGF3+1+2). MST studies have led to the characterization of equilibrium dissociation constants (Kd) for MUC4β-ErbB2 (7–25 nM) and MUC4EGF3+1+2/ErbB2 (65–79 nM) complexes. This work provides new information regarding the MUC4-ErbB2 interaction at the biophysical level and also confirms that the presence of the three EGF domains of MUC4 is sufficient to provide efficient interaction. This technological approach will be very useful in the future to validate small molecule binding affinities targeting MUC4-ErbB2 complex for drug discovery development in cancer. It will also be of high interest for the other known membrane mucins forming oncogenic complexes with ErbBs at the cancer cell surface.

A study of the histopathological features of alopecias on transverse sections of scalp biopsies

Background:Transverse sections of scalp biopsies are performed for the assessment of alopecias and are considered advantageous over vertical sections.Aim:The aim was to study the histopathological features of alopecias on transverse sections of scalp biopsies.Methods:It was a descriptive study. Clinically confirmed cases of noncicatricial and cicatricial alopecias were subjected to 4 mm scalp biopsies, which were sectioned transversely and analyzed. Biopsies obtained from occipital region of androgenetic alopecia (AGA) cases were taken as controls.Results:Biopsies from 41 cases were assessed, including male and female AGA, alopecia areata (AA), trichotillomania, lichen planopilaris (LPP), discoid lupus erythematosus (DLE), and folliculitis decalvans (FD). Normal scalp (control) biopsies showed the median total number of hair follicles of 35 (32–37), anagen:telogen/catagen ratio of 17.5 (16.5–31), and terminal:vellus ratio of 15 (10.7–17.5). In AGA and AA, miniaturization and shift toward telogen and catagen hair were consistently observed. Peribulbar inflammation was seen in two-third of AA. Trichotillomania showed increased catagen hair and numerous pigment casts. In DLE, besides perifollicular inflammation, prominent peri-arrector pili and peri-eccrine inflammation were observed. Type of inflammatory infiltrate was similar in DLE and LPP (lymphocytic), whereas FD showed neutrophilic and plasma cell infiltrate, both around follicles and interstitially. Basal cell damage in the follicles and pigment incontinence were seen in majority of DLE and LPP patients. DLE also showed basement membrane thickening, mucin deposition, and telangiectasia. Reduction/absence of sebaceous glands and perifollicular fibrosis were observed in almost all cicatricial alopecias.Conclusion:Transverse sectioning may be a useful tool in the diagnosis of alopecias.

Serum tumor-associated glycoprotein 72, a helpful predictor of lymph nodes invasion in esophagogastric junction adenocarcinoma

Disruption of cell-cell junction and adhesion to vessels are crucial steps in tumor metastasis. Tumor-associated glycoprotein 72 (TAG-72) is a crucial membrane mucin in gastroesophageal mucosa for microenvironment contact with cells. Thus, the TAG-72 value may be an indicator of the malignant involvement of lymph nodes in esophagogastric junction adenocarcinoma (EGAC) patients. Of the 183 patients suspected as gastroesophageal neoplasms, 129 were subsequently diagnosed as EGAC, and 54 were subsequently diagnosed as benign gastroesophageal diseases by imageological or/and histological examination. After we obtained preoperative serum TAG-72 values, the relationship between serum TAG-72 and lymphatic metastasis status, extent of invaded lymph nodes and clinical stage was tested using Spearman correlation analysis and χ2 tests. Compared with those in patients who suffered either benign gastroesophageal diseases or preinvasive carcinoma, the median serum TAG-72 values were statistically higher in EGAC patients with positive lymph nodes (Kruskal-Wallis test; P < 0.001). Serum TAG-72 values were significantly correlated with Lymph Node Ratio (LNR) (Spearman correlation; P < 0.001). Using corresponding ROC (95% CI = 0.621–0.783, P < 0.0001), serum TAG-72 values with an optimal cut-off (2.2 kU/mL) showed a sensitivity of 0.632 and a specificity of 0.690 for predicting malignant lymph node involvement in EGAC. These results suggest that the serum TAG-72 value is a clinically helpful predictor of lymph nodes invasion in resectable EGAC.

MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease

BackgroundLung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models.MethodsMUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models.ResultsMUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone.ConclusionsThese results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.

Mucin 1 deficiency mediates corticosteroid insensitivity in asthma.

The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n=27), controlled mild asthma (n=16), and healthy subjects (n=13). IL-8, MMP9, and GM-CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines. Mucin 1-CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P<0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (ρ=-0.71; P<0.0001). Dexamethasone showed lower anti-inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)-α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1-CT/GRα complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti-inflammatory effects of dexamethasone. Mucin 1-CT modulates corticosteroid efficacy invitro and invivo asthma models.

Effect of Host Human Products on Natural Transformation in Acinetobacter baumannii.

Our previous data show that serum albumin can trigger natural transformation in Acinetobacter baumannii. However, extracellular matrix/basal membrane components, norepinephrine, and mucin did not have a significant effect on this process. Therefore, the effect of human products appears to be albumin specific, as both BSA and HSA have been shown to increase of natural transformation.

Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer

Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer

Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer.

Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. While it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically-engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with red and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.

A Case of Sclerosing Epithelioid Fibrosarcoma With EWSR1 Translocation

Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma that commonly occurs in soft tissue. Since its original description in 1995, studies have revealed cytogenetic similarities with low-grade fibromyxoid sarcoma (LGFMS) and hybrid tumor composed of SEF and LGFMS. We report a case of SEF with EWSR1 gene rearrangement. A 62-year-old man had complained of a soft tissue mass in the left part of the buttock for 4 months. Imaging studies revealed a 6-cm mass in the left gluteus muscle, which was excised. Microscopically, the tumor was composed of short, spindle-shaped tumor cells with bland oval or polygonal nuclei arranged in cords and clusters with intervening sclerosing collagen matrix. Immunohistochemically, the tumor cells were positive for epithelial membrane antigen and mucin 4. Fluorescence in situ hybridization demonstrated split signals for the EWSR1 gene. These findings were consistent with SEF. Some SEFs have been reported to have shared features with LGFMS; those lesions are termed “hybrid tumors”; however, recent studies revealed that there is a pure type of SEF, which harbors EWSR1 gene rearrangements, distinct from the chromosomal abnormalities seen in LGFMS. The present case is a histologically pure SEF with EWSR1 gene translocation; its cytogenetic profile suggests that pure type SEF is a separate entity distinct from LGFMS and hybrid tumor.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma

Genetically modified Tcells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR Tcell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR Tcells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of Tcell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR Tcells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered Tcells.