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Background: PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood. Methods: The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients. Results: We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis. Conclusions: We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response. [ABSTRACT FROM AUTHOR]

Introduction: We have recently demonstrated that Sox10-expressing (Sox10+) cells give rise to mainly type-III neuronal taste bud cells that are responsible for sour and salt taste. The two tissue compartments containing Sox10+ cells in the surrounding of taste buds include the connective tissue core of taste papillae and von Ebner's glands (vEGs) that are connected to the trench of circumvallate and foliate papillae. Methods: In this study, we performed single cell RNA-sequencing of the epithelium of Sox10-Cre/tdT mouse circumvallate/vEG complex and used inducible Cre mouse models to map the cell lineages of vEGs and/or connective tissue (including stromal and Schwann cells). Results: Transcriptomic analysis indicated that Sox10 expression was enriched in the cell clusters of vEG ducts that contained abundant proliferating cells, while Sox10-Cre/tdT expression was enriched in type-III taste bud cells and vEG ductal cells. In vivo lineage mapping showed that the traced cells were distributed in circumvallate taste buds concurrently with those in the vEGs, but not in the connective tissue. Moreover, multiple genes encoding pathogen receptors were enriched in the vEG ducts hosting Sox10+ cells. Discussion: Our data supports that it is the vEGs, not connective tissue core, that serve as the niche of Sox10+ taste bud progenitors. If this is also true in humans, our data indicates that vEG duct is a source of Sox10+ taste bud progenitors and susceptible to pathogen infections. [ABSTRACT FROM AUTHOR]

In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10+ cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest‐derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10‐driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle‐deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development. [ABSTRACT FROM AUTHOR]

Several members of the SRY-related HMG-box (SOX) protein family are implicated in tumorigenesis, metastasis, and regulation of the tumor microenvironment. SOX10, which is involved in neural crest cell migration and differentiation, has long been recognized a sensitive and specific immunohistochemical (IHC) marker in the diagnosis of melanoma in humans. However, expression of SOX10 in other tumor types has infrequently been evaluated in humans until recently and has not been thoroughly investigated in the dog. Our aim was to characterize the expression of SOX10 in canine neoplasms to objectively assess its value as a diagnostic IHC marker. Immunohistochemistry for SOX10 was performed on 437 archived, formalin-fixed paraffin-embedded tissues from representative canine neoplasms of ectodermal (15 tumor types), mesodermal (13 tumor types), endodermal (8 tumor types), and mixed/unknown (7 tumor types) embryologic origin. Oral and cutaneous tumors of melanocytic origin were used as positive controls. Intense SOX10 immunolabeling was observed in most tumors of ectodermal origin, including consistent expression in mammary carcinomas, and gliomas. Embryonal and hair follicle neoplasms inconsistently exhibited strong nuclear immunolabeling. Oral fibrosarcomas and undifferentiated oral sarcomas both inconsistently exhibited moderate to strong nuclear immunolabeling. Neoplasms of mesodermal and endodermal origin lacked immunolabeling. Salivary carcinomas, representing an unknown/mixed embryologic origin, were strongly labeled. SOX10 expression is not limited to melanomas, but is expressed by canine tumors of diverse tissues and embryologic derivation. Importantly, expression of SOX10 by a subset of oral sarcomas impairs its value as a marker for spindle cell oral melanomas. [ABSTRACT FROM AUTHOR]

Purpose: Schwannoma is a rare mesenchymal tumor. In this study, we analyzed clinicopathologically 99 schwannomas.This retrospective study delves into the clinical, pathological, and immunohistochemical dimensions of abdominal schwannomas. Results: A cohort of 99 cases, comprising 4 malignant and 95 benign schwannomas, was meticulously examined. Clinical analysis revealed a notable gender distribution (1:1.7, male to female) and an average age of 58.5 years. The majority of cases were asymptomatic. A cohort of 99 cases, comprising 4 malignant and 95 benign schwannomas, was meticulously examined. Clinical analysis revealed a notable gender distribution (1:1.7, male to female) and an average age of 58.5 years. The majority of cases were asymptomatic. Tumor sizes ranged from 0.5 to 30 cm, with distinct locations in the stomach for most benign cases and the abdomen/small intestine for malignancies. Initial misdiagnoses were frequent. Pathological evaluations revealed distinct features, including Antoni A and B patterns, spindle cells, and lymphatic sheath structures in benign schwannomas. Malignant cases exhibited atypical cells, ulcers, and invasive growth. Immunohistochemical markers, such as S100, SOX10, and vimentin, consistently demonstrated positivity by contributing to accurate diagnoses. Treatment outcomes indicated a poor prognosis in malignant cases, with overall survival ranging from 10 to 41 months. Conversely, benign cases displayed no recurrence or metastasis during follow‐up, despite atypical behaviors. Conclusion: This study underscores the rarity of abdominal schwannomas and underscores the need for a comprehensive diagnostic morphology and immunohistochemistry. SOX10 emerges as a crucial and specific marker for accurate diagnosis. Further research is imperative to refine diagnostic protocols and enhance our understanding of the clinical behavior of abdominal schwannomas. The study conducted a retrospective, large‐scale analysis of 99 cases of abdominal schwannomas. It unveiled the rare occurrence of malignant schwannomas in the small intestine and abdominal cavity, posing challenges in diagnosis and differential diagnosis. The presentation of novel histological and immunohistochemical features in the cases provides crucial insights for the accurate diagnosis of schwannomas. A detailed analysis of both benign and malignant cases establishes a foundation for future improvements in clinical management and treatment strategies. [ABSTRACT FROM AUTHOR]

Leucine-rich glioma-inactivated protein 1 (LGI1), a secretory protein in the brain, plays a critical role in myelination; dysfunction of this protein leads to hypomyelination and white matter abnormalities (WMAs). Here, we hypothesized that LGI1 may regulate myelination through binding to an unidentified receptor on the membrane of oligodendrocytes (OLs). To search for this hypothetic receptor, we analyzed LGI1 binding proteins through LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry. An OL-specific membrane protein, the oligodendrocytic myelin paranodal and inner loop protein (OPALIN), was identified. Conditional knockout (cKO) of OPALIN in the OL lineage caused hypomyelination and WMAs, phenocopying LGI1 deficiency in mice. Biochemical analysis revealed the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation in Opalin cKO mice. Moreover, virus-mediated re-expression of OPALIN successfully restored myelination in Opalin cKO mice. In contrast, re-expression of LGI1-unbound OPALIN_K23A/D26A failed to reverse the hypomyelination phenotype. In conclusion, our study demonstrated that OPALIN on the OL membrane serves as an LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in orchestrating OL differentiation and myelination. [ABSTRACT FROM AUTHOR]

Breast carcinoma with tubulopapillary features is a newly described entity associated with poor prognosis with only 14 tumors reported in the literature. We report 2 additional tumors and identify novel immunohistochemical and molecular features of the tumor. The first tumor was from a 72-year-old woman with nonmetastatic breast carcinoma and the second was from a 32-year-old woman with metastatic breast carcinoma who received neoadjuvant therapy. Both tumors had high-grade nuclear features with a distinctive morphology characterized by infiltrating open glands with intratubular papillary and micropapillary projections in >90% of the invasive carcinoma. In addition to the usual predictors of aggressive behavior, both tumors showed a high expression of p16 and SOX10, which has not been previously described. Targeted tumor sequencing revealed pathogenic variants of TP53 in both tumors, in agreement with previous reports. Prior studies have shown a correlation between p16 and SOX10 expression with high-grade features and worse prognosis; typically seen in triple-negative carcinomas as demonstrated in both of our tumors. However, not all reported tumors of breast carcinoma with tubulopapillary features have demonstrated a triple-negative profile as there are a few reports of tumors with estrogen receptor and/or human epidermal growth factor 2 expression. Due to their distinct morphologic and molecular characteristics, breast carcinoma with tubulopapillary features may represent a new breast cancer histologic subtype. [ABSTRACT FROM AUTHOR]

BackgroundSchwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.MethodsWe performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.ResultsWe identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.ConclusionsWe thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Abstract Background PD-L1 expression on cancer cells is an important mechanism of tumor immune escape, and immunotherapy targeting the PD-L1/PD1 interaction is a common treatment option for patients with melanoma. However, many patients do not respond to treatment and novel predictors of response are emerging. One suggested modifier of PD-L1 is the p53 pathway, although the relationship of p53 pathway function and activation is poorly understood. Methods The study was performed on human melanoma cell lines with various p53 status. We investigated PD-L1 and proteins involved in IFNγ signaling by immunoblotting and mRNA expression, as well as membrane expression of PD-L1 by flow cytometry. We evaluated differences in the ability of NK cells to recognize and kill target tumor cells on the basis of p53 status. We also investigated the influence of proteasomal degradation and protein half-life, IFNγ signaling and p53 activation on biological outcomes, and performed bioinformatic analysis using available data for melanoma cell lines and melanoma patients. Results We demonstrate that p53 status changes the level of membrane and total PD-L1 protein through IRF1 regulation and show that p53 loss influences the recently discovered SOX10/IRF1 regulatory axis. Bioinformatic analysis identified a dependency of SOX10 on p53 status in melanoma, and a co-regulation of immune signaling by both transcription factors. However, IRF1/PD-L1 regulation by p53 activation revealed complicated regulatory mechanisms that alter IRF1 mRNA but not protein levels. IFNγ activation revealed no dramatic differences based on TP53 status, although dual p53 activation and IFNγ treatment confirmed a complex regulatory loop between p53 and the IRF1/PD-L1 axis. Conclusions We show that p53 loss influences the level of PD-L1 through IRF1 and SOX10 in an isogenic melanoma cell model, and that p53 loss affects NK-cell cytotoxicity toward tumor cells. Moreover, activation of p53 by MDM2 inhibition has a complex effect on IRF1/PD-L1 activation. These findings indicate that evaluation of p53 status in patients with melanoma will be important for predicting the response to PD-L1 monotherapy and/or dual treatments where p53 pathways participate in the overall response. Graphical Abstracts

PRRX1‐fused mesenchymal neoplasm is a recently identified, rare subcutaneous soft tissue neoplasm that is characterized by fusion of PRRX1 (exon 1) with NCOA1 (exon 13) in the majority of reported cases. Although initially considered to be fibroblastic, a possibility of neural or neuroectodermal differentiation has been suggested in a subset of cases. We report a 26‐year‐old female with a 4.0 cm painless mass located in the subcutis of the left thigh. Microscopically, the tumor was well‐circumscribed and multinodular and was composed of relatively monomorphic ovoid to spindle cells arranged in loose fascicles, trabeculae, and cords within alternating myxoid and fibrous matrix, and vascularized stroma. Mitotic figures were scarce and necrosis was not observed. By immunohistochemistry, the neoplastic cells demonstrated focal co‐expression of S100 protein and SOX10 and were negative for epithelial membrane antigen, smooth muscle actin, desmin, CD34, STAT6, HMB45, Melan‐A, and MUC4. The expression of Rb1 was retained. Targeted RNA‐sequencing identified a novel transcript fusion of PRRX1 (exon 1)::NCOA1 (exon 15), which was further confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. The tumor was narrowly excised and no tumor recurrence or metastasis was identified after 13 months of follow‐up. In summary, we report a new case of PRRX1‐fused mesenchymal neoplasm, expanding the molecular genetic spectrum and providing further support for possible neural or neuroectodermal differentiation of this emerging soft tissue tumor entity. [ABSTRACT FROM AUTHOR]

The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the Tle4 gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression. [ABSTRACT FROM AUTHOR]

Abstract Purpose Schwannoma is a rare mesenchymal tumor. In this study, we analyzed clinicopathologically 99 schwannomas.This retrospective study delves into the clinical, pathological, and immunohistochemical dimensions of abdominal schwannomas. Results A cohort of 99 cases, comprising 4 malignant and 95 benign schwannomas, was meticulously examined. Clinical analysis revealed a notable gender distribution (1:1.7, male to female) and an average age of 58.5 years. The majority of cases were asymptomatic. A cohort of 99 cases, comprising 4 malignant and 95 benign schwannomas, was meticulously examined. Clinical analysis revealed a notable gender distribution (1:1.7, male to female) and an average age of 58.5 years. The majority of cases were asymptomatic. Tumor sizes ranged from 0.5 to 30 cm, with distinct locations in the stomach for most benign cases and the abdomen/small intestine for malignancies. Initial misdiagnoses were frequent. Pathological evaluations revealed distinct features, including Antoni A and B patterns, spindle cells, and lymphatic sheath structures in benign schwannomas. Malignant cases exhibited atypical cells, ulcers, and invasive growth. Immunohistochemical markers, such as S100, SOX10, and vimentin, consistently demonstrated positivity by contributing to accurate diagnoses. Treatment outcomes indicated a poor prognosis in malignant cases, with overall survival ranging from 10 to 41 months. Conversely, benign cases displayed no recurrence or metastasis during follow‐up, despite atypical behaviors. Conclusion This study underscores the rarity of abdominal schwannomas and underscores the need for a comprehensive diagnostic morphology and immunohistochemistry. SOX10 emerges as a crucial and specific marker for accurate diagnosis. Further research is imperative to refine diagnostic protocols and enhance our understanding of the clinical behavior of abdominal schwannomas.

IntroductionWe have recently demonstrated that Sox10-expressing (Sox10+) cells give rise to mainly type-III neuronal taste bud cells that are responsible for sour and salt taste. The two tissue compartments containing Sox10+ cells in the surrounding of taste buds include the connective tissue core of taste papillae and von Ebner’s glands (vEGs) that are connected to the trench of circumvallate and foliate papillae.MethodsIn this study, we performed single cell RNA-sequencing of the epithelium of Sox10-Cre/tdT mouse circumvallate/vEG complex and used inducible Cre mouse models to map the cell lineages of vEGs and/or connective tissue (including stromal and Schwann cells).ResultsTranscriptomic analysis indicated that Sox10 expression was enriched in the cell clusters of vEG ducts that contained abundant proliferating cells, while Sox10-Cre/tdT expression was enriched in type-III taste bud cells and vEG ductal cells. In vivo lineage mapping showed that the traced cells were distributed in circumvallate taste buds concurrently with those in the vEGs, but not in the connective tissue. Moreover, multiple genes encoding pathogen receptors were enriched in the vEG ducts hosting Sox10+ cells.DiscussionOur data supports that it is the vEGs, not connective tissue core, that serve as the niche of Sox10+ taste bud progenitors. If this is also true in humans, our data indicates that vEG duct is a source of Sox10+ taste bud progenitors and susceptible to pathogen infections.

Abstract Background HSCR is a complex genetic disorder characterized by the absence of ganglion cells in the intestine, leading to a functional obstruction. It is due to a disruption of complex signaling pathways within the gene regulatory network (GRN) during the development of the enteric nervous system (ENS), including SRY-Box Transcription Factor 10 (SOX10) and REarranged during Transfection (RET). This study evaluated the expressions of SOX10 and RET in HSCR patients in Indonesia. Methods Total RNA of 19 HSCR ganglionic and aganglionic colons and 16 control colons were analyzed using quantitative real-time polymerase chain reaction for SOX10 and RET with GAPDH as the reference gene. Livak’s method (2−ΔΔC T) was used to determine the expression levels of SOX10 and RET. Results Most patients were males (68.4%), in the short aganglionosis segment (78.9%), and had undergone transanal endorectal pull-through (36.6%). There were significant upregulated SOX10 expressions in both ganglionic (2.84-fold) and aganglionic (3.72-fold) colon of HSCR patients compared to controls’ colon (ΔCT 5.21 ± 2.04 vs. 6.71 ± 1.90; p = 0.032; and ΔCT 4.82 ± 1.59 vs. 6.71 ± 1.90; p = 0.003; respectively). Interestingly, the RET expressions were significantly downregulated in both ganglionic (11.71-fold) and aganglionic (29.96-fold) colon of HSCR patients compared to controls’ colon (ΔCT 12.54 ± 2.21 vs. 8.99 ± 3.13; p = 0.0004; and ΔCT 13.90 ± 2.64 vs. 8.99 ± 3.13; p = 0.0001; respectively). Conclusions Our study shows aberrant SOX10 and RET expressions in HSCR patients, implying the critical role of SOX10 and RET in the pathogenesis of HSCR, particularly in the Indonesian population. Our study further confirms the involvement of SOX10-RET within the GNR during the ENS development.

Objectives: This study aimed to identify the causative variants in a patient with Waardenburg syndrome (WS) type 2 using whole exome sequencing (WES). Methods: The clinical features of the patient were collected. WES was performed on the patient and his parents to screen causative genetic variants and Sanger sequencing was performed to validate the candidate mutation. The AlphaFold2 software was used to predict the changes in the 3D structure of the mutant protein. Western blotting and immunocytochemistry were used to determine the SOX10 mutant in vitro. Results: A de novo variant of SOX10 gene, NM_006941.4: c.707_714del (p. H236Pfs*42), was identified, and it was predicted to disrupt the wild-type DIM/HMG conformation in SOX10. In-vitro analysis showed an increased level of expression of the mutant compared to the wild-type. Conclusions: Our findings helped to understand the genotype-phenotype association in WS2 cases with SOX10 mutations. [ABSTRACT FROM AUTHOR]

Aims: The SOX10 transcription factor is important for the maturation of oligodendrocytes involved in central nervous system (CNS) myelination. Currently, very little information exists about its expression and potential use in CNS tumour diagnoses. The aim of our study was to characterize the expression of SOX10 in a large cohort of CNS tumours and to evaluate its potential use as a biomarker. Methods: We performed immunohistochemistry (IHC) for SOX10 and OLIG2 in a series of 683 cases of adult‐ and paediatric‐type CNS tumours from different subtypes. The nuclear immunostaining results for SOX10 and OLIG2 were scored as positive (≥10% positive tumour cells) or negative. Results: OLIG2 and SOX10 were positive in diffuse midline gliomas (DMG), H3‐mutant, and EZHIP‐overexpressed. However, in all DMG, EGFR‐mutant, SOX10 was constantly negative. In diffuse paediatric‐type high‐grade gliomas (HGG), all RTK1 cases were positive for both OLIG2 and SOX10. RTK2 cases were all negative for both OLIG2 and SOX10. MYCN cases variably expressed OLIG2 and were all immunonegative for SOX10. In glioblastoma, IDH‐wildtype, OLIG2 was mostly positive, but SOX10 was variably expressed, depending on the epigenetic subtype. All circumscribed astrocytic gliomas were positive for both OLIG2 and SOX10 except pleomorphic xanthoastrocytomas, astroblastomas, MN1‐altered, and subependymal giant cell astrocytomas. SOX10 was negative in ependymomas, meningiomas, pinealoblastomas, choroid plexus tumours, intracranial Ewing sarcomas, and embryonal tumours except neuroblastoma, FOXR2‐activated. Conclusion: To conclude, SOX10 can be incorporated into the IHC panel routinely used by neuropathologists in the diagnostic algorithm of embryonal tumours and for the subtyping of paediatric and adult‐type HGG. [ABSTRACT FROM AUTHOR]

Introduction. Triple negative breast carcinomas are characterized by a lack of hormone receptor and HER2 expression and inconsistent expression of breast-specific immunohistochemical markers. The expression of many site-specific markers in these tumors is largely unknown. The objective of the study was to examine the expression of widely used immunohistochemical markers on a large cohort of triple negative breast cancer. Methods. Sections from tissue microarrays were stained with 47 markers using routine protocols. Most markers were scored using a modified Allred method. ATRX, BAP1, SMAD4, e-cadherin, and beta-catenin were scored as retained or lost. Mammaglobin was considered positive if there was at least moderate intensity staining in any tumor cells. P16 was scored as overexpressed or not overexpressed; p53 was scored as wildtype, overexpressed, null, or cytoplasmic. Results. The cohort consisted of 639 tumors including 601 primary and 32 metastases. Overall, 96% expressed GATA3, mammaglobin, and/or SOX10 while 97% of no special type tumors expressed this panel. Carcinoma of apocrine differentiation demonstrated an AR positive, SOX10 negative, K5 negative/focal immunophenotype. PAX8 (SP348), WT1, Napsin A, and TTF1 (8G7G3/1) were never or rarely expressed while CA9, CDX2, NKX3.1, SATB2 (SATBA410), synaptophysin, and vimentin were variably expressed. Conclusions. Almost all TNBC express at least 1 of the 3 IHC markers: GATA3, mammaglobin, and/or SOX10. Carcinoma of apocrine differentiation is characterized by an AR positive, SOX10 negative, K5 negative or focal immunophenotype. Cautious interpretation of so-called site-specific markers, with knowledge of antibody clones, is required in excluding the diagnosis of triple negative breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to characterize soft tissue tumors/sarcomas (STSs) occurring on the faces of cats using histomorphology, immunohistochemistry, and molecular (PCR) techniques. By examining 34 tumors from 29 cats, we found that many were peripheral nerve sheath tumors (PNSTs), identified by specific protein markers. Interestingly, only a few tumors thought to be sarcoids were confirmed by testing for BPV14. This highlights the need for careful diagnostic methods to correctly identify these tumors. Some tumors appeared as unusual lesions on the face, not typical masses, pointing out an important clue for clinicians. The study also introduces a new observation in tumor cells' pattern and underscores the value of the Sox10 marker in diagnosing PNSTs in cats, offering new insights for veterinary pathologists. Soft tissue tumors/sarcomas (STSs) in felines, encompassing a variety of mesenchymal tumors with similar histomorphological features, present diagnostic challenges due to their diverse cellular origins and the overlap with other tumor types such as feline sarcoid. This study aimed to delineate the clinical, histomorphological, and immunohistochemical characteristics of 34 feline facial spindle cell tumors affecting 29 cats, including testing for bovine papillomavirus type 14 (BPV14), the virus causing feline sarcoids. Only five out of 12 tumors previously diagnosed as feline sarcoids based on histomorphology were confirmed by PCR for BPV14, underscoring the importance of comprehensive diagnostic approaches to accurately distinguish between STSs and feline sarcoids. This study shows that most facial spindle cell tumors were compatible with peripheral nerve sheath tumors (PNSTs) based on positive immunohistochemical staining for Sox10 and other immunohistochemical markers such as GFAP, NSE, and S100. Some of these tumors displayed as multiple independent masses on the face or as erosive and ulcerative lesions without obvious mass formation, an atypical presentation and an important highlight for general practitioners, dermatologists, and oncologists. This study also describes periadnexal whorling of neoplastic cells as a novel histomorphologic finding in feline facial PNSTs and emphasizes Sox10 as a useful complementary immunohistochemical marker for the diagnosis of facial PNST in cats, providing valuable insights for veterinary pathologists. [ABSTRACT FROM AUTHOR]

Desmoplastic melanoma (DM), a type of spindle cell melanoma separated into pure desmoplastic melanoma (PDM) and mixed desmoplastic melanoma (MDM) subtypes, can be a diagnostic challenge and easily confused for dermal scar, especially PDM. We report a 65‐year‐old white man who received a left thumb amputation after an initial biopsy for melanoma, an unclassified type with epithelioid morphology. The amputation and sentinel lymph node specimens were significant for residual melanoma with epithelioid morphology, dermal scar, and a slightly expanded "scar‐like" capsular area in one of seven lymph nodes, which was diffusely positive for SOX10 on reflex sentinel lymph node immunohistochemical protocol. On re‐review of the amputation "scar" like area, a subsequent SOX10 stain confirmed the diagnosis of MDM in this area with epithelioid and spindle cell morphology, significantly upgrading the tumor stage. We share this case to highlight: (i) MDM, although exceptionally uncommon, can result in a pure spindle cell lymph node metastasis, (ii) to encourage increased utilization of SOX10 to assess sentinel lymph node biopsies, especially in the context of melanomas with a spindle cell component, and (iii) share an example of inattentional blindness which was fortunately identified by reflex sentinel lymph node immunohistochemical protocols. [ABSTRACT FROM AUTHOR]

To investigate the molecular mechanisms underlying the differences in iris color in quail, the transcriptome of iris tissue from black quail and Korean quail at day 10 of hatching was RNA sequenced in this study. The differentially expressed genes (DEGs) were screened, functionally annotated and enriched after the quality control and mapping of the raw data. RT‐qPCR validation was performed using EIF2S3 as an internal reference gene. The screened SNPs were studied by bioinformatics analysis and iris color correlation analysis. The results showed that there were 425 upregulated genes and 364 downregulated genes in 789 DEGs. Gene Ontology (GO) enrichment analysis revealed that 139 DEGs were significantly enriched in 154 GO terms. The Kyoto Encyclopedia of Genes and Genomes enrichment results showed that the Notch signaling pathway, melanogenesis and tyrosine metabolism were associated with pigment synthesis (p < 0.05). The expression levels of the ASIP, MLPH, PMEL, TYR and SOX10 genes were significantly different in black quail iris and Korean quail iris, as verified by RT‐qPCR. The SOX10 gene c.324G>C mutation, which caused the replacement of p.Glu108Asp, had a highly significant correlation with iris color in black quail and Korean quail, which may be one of the reasons for different in iris color between these two quail species. [ABSTRACT FROM AUTHOR]

IntroductionWaardenburg syndrome (WS) is a genetic disorder characterized by hearing loss, hypopigmentation, and distinct facial features. Despite > 60% molecular diagnosis rate for WS patients, pathogenic variants within coding regions are predominant, with few non-coding copy number variations (CNVs) reported.MethodsIn this study, we performed whole genome sequencing (WGS) on 59 undiagnosed WS patients and analyzed the CNVs within the promoter and enhancer regions of the SOX10 gene.ResultsWe identified five novel pathogenic deletions ranging from 448 bp to 70 kb upstream of SOX10. Two deletions were in the enhancer region, while three were in the promoter and 5'UTR region. These CNVs manifested as WS type II in eight patients from five unrelated families, demonstrating phenotypic heterogeneity. Furthermore, analysis of CNV1 within the enhancer region suggested a potential mechanism involving Alu-mediated non-allelic homologous recombination (NAHR).ConclusionOur findings extend the mutation spectrum of the SOX10 gene and elucidate the pathogenic role of CNVs in cis-regulatory elements, particularly variations in enhancer and promoter regions, thereby enhancing clinical gene detection and interpretation of non-coding regions.

The embryonic development of neural crest cells and subsequent tissue differentiation are intricately regulated by specific transcription factors. Among these, SOX10, a member of the SOX gene family, stands out. Located on chromosome 22q13, the SOX10 gene encodes a transcription factor crucial for the differentiation, migration, and maintenance of tissues derived from neural crest cells. It plays a pivotal role in developing various tissues, including the central and peripheral nervous systems, melanocytes, chondrocytes, and odontoblasts. Mutations in SOX10 have been associated with congenital disorders such as Waardenburg–Shah Syndrome, PCWH syndrome, and Kallman syndrome, underscoring its clinical significance. Furthermore, SOX10 is implicated in neural and neuroectodermal tumors, such as melanoma, malignant peripheral nerve sheath tumors (MPNSTs), and schwannomas, influencing processes like proliferation, migration, and differentiation. In mesenchymal tumors, SOX10 expression serves as a valuable marker for distinguishing between different tumor types. Additionally, SOX10 has been identified in various epithelial neoplasms, including breast, ovarian, salivary gland, nasopharyngeal, and bladder cancers, presenting itself as a potential diagnostic and prognostic marker. However, despite these associations, further research is imperative to elucidate its precise role in these malignancies.

Objective To compare the otological phenotypic characteristics induced by Waardenburg syndrome mutation SOX10 p.R106W in mouse, miniature pig and human, and to construct a mouse model harboring orthologous human SOX10 p.R106W mutation. Methods By comparing the amino acid sequences of SOX10 proteins from human, miniature pig and mouse, the mouse orthologous site corresponding to human SOX10 p.R106W mutation was identified, and the nucleic acid mutation Sox10 c.316A > T coding Sox10 p.R106W was precisely introduced into the orthologous site of mouse Sox10 coding sequence by CRISPR/Cas9-induced homologous recombination. Characteristics of otological phenotypes were assessed by auditory brainstem response test and cochlear tissue histology. mRNA sequencing was conducted on cochlear tissues, and differential expressed genes (DEGs) were accepted gene ontology (GO) analysis. The correlation between DEGs and Sox10 was analyzed through String database. Results The gene-edited mice harboring Sox10 c.316A > T (Sox10 p.R106W) mutation were successfully generated. The skin of gene-edited mice exhibited white spots and stable heterozygous inheritance. Sox10 c.316A > T/+ mutant mice showed no notable difference in cochlea histological structure as well as response to acoustic stimulation, compared with wild type (WT) littermates. Transcriptomic analysis revealed that Sox10 c.316A > T/+ mutant mice had 323 upregulated genes in concomitant with 283 downregulated genes. GO analysis showed that upregulated genes were associated with immunity while downregulated genes were associated with neurological functions. Five genes, neurofilament heavy polypeptide(Nefh)、fatty acid 2-hydroxylase(Fa2h)、gap junction protein beta 1(Gjb1)、nerve growth factor receptor(Ngfr) and zinc finger protein 536(Zfp536) were correlated with Sox10, but had no relationship with cochlear development and function. Conclusion Sox10 p.R106W mutant mouse model is successfully established using CRISPR/Cas9 system. Compared with WT mice, the gene-edited mice have no difference in otological phenotypes, while there is significant difference in disease phenotype induced by these mutation in human and miniature pig.

Targeted therapy resistance frequently develops in melanoma due to intratumor heterogeneity and epigenetic reprogramming. This also typically induces cross-resistance to immunotherapies. Whether this includes additional modes of therapy has not been fully assessed. We show that co-treatments of MAPKi with VSV-based oncolytics do not function in a synergistic fashion; rather, the MAPKis block infection. Melanoma resistance to vemurafenib further perturbs the cells' ability to be infected by oncolytic viruses. Resistance to vemurafenib can be induced by the loss of SOX10, a common proliferative marker in melanoma. The loss of SOX10 promotes a cross-resistant state by further inhibiting viral infection and replication. Analysis of RNA-seq datasets revealed an upregulation of interferon-stimulated genes (ISGs) in SOX10 knockout populations and targeted therapy-resistant cells. Interestingly, the induction of ISGs appears to be independent of type I IFN production. Overall, our data suggest that the pathway mediating oncolytic resistance is due to the loss of SOX10 during acquired drug resistance in melanoma. [ABSTRACT FROM AUTHOR]

Introduction: The gastrointestinal neuroectodermal tumor (GNET) is a rare mesenchymal tumor mainly arising in the gastrointestinal tract. Case Presentation: Herein, we describe a case of GNET that had been previously diagnosed as metastatic primitive neuroectodermal tumor (PNET) to the lung and liver and received 30 cycles of adjuvant chemotherapy. The physical exam showed a palpable mass in the lower right quadrant of the abdomen. The tumor mass was composed of diffuse sheets of epithelioid tumor cells, in which osteoclast-like giant cells scattered unevenly. Immunohistochemically, the tumor cells were diffusely positive for SOX10, CD99, and CD56, patchy positive forpan-CK, and negative fordesmin, HMB-45, Melan-A, and chromogranin. Conclusions: Consistent with previous studies that reported a secondary GNET following chemotherapy, we assume that the chemotherapy might trigger the tumorigenesis of GNET in this case. [ABSTRACT FROM AUTHOR]

Waardenburg syndrome (WS) is characterized by the association of sensorineural hearing loss and pigmentation abnormalities. Among the four types, WS Type 2 (WS2) is the only one without a remarkable distinguishing feature. Here, we report a patient initially diagnosed with WS2 who exhibits a 446 kb mosaic duplication in chromosome 22q13.1, encompassing SOX10, and detected using whole genome sequencing in a trio. The patient, a 46,XY boy, presents with profound bilateral sensorineural hearing loss, right heterochromia iridium, left bright blue iris, and skin‐depigmented areas in the abdomen and limbs. Vestibular and imaging tests are normal, without inner ear or olfactory bulb malformations. Bilateral cochlear implantation did not prevent language and speech delays. Moderate congenital chronic constipation and neurodevelopmental difficulties were also present. Given the few genes included in this duplicated region (only one OMIM gene with dominant inheritance), this report provides further delineation of the phenotype related to duplications encompassing the entire SOX10 gene. [ABSTRACT FROM AUTHOR]

Purpose: Intestinal neuronal dysplasia (IND) is a congenital anomaly affecting gastrointestinal neural innervation, but the pathogenesis remains unclear. The homozygous Ncx/Hox11L.1 knockout (Ncx−/−) mice exhibit megacolon and enteric ganglia anomalies, resembling IND phenotypes. Sox10-Venus transgenic mouse were used to visualize enteric neural crest cells in real time. This study aims to establish a novel mouse model of Sox10-Venus+/Ncx−/− mouse to study the pathogenesis of IND. Methods: Sox10-Venus+/Ncx−/− (Ncx−/−) (n = 8) mice and Sox10-Venus+/Ncx+/+ controls (control) (n = 8) were euthanized at 4–5 weeks old, and excised intestines were examined with fluorescence microscopy. Immunohistochemistry was performed on tissue sections with neural marker Tuj1. Results: Ncx−/− mice exhibited dilated cecum and small intestine. Body weight of Ncx−/− mice was lower with higher ratio of small intestine length relative to body weight. The neural network (Sox10-Venus) was observed along the intestine wall in Ncx−/− and control mice without staining. Ectopic and increased expression of Tuj1 was observed in both small intestine and proximal colon of Ncx−/− mice. Conclusion: This study has established a reliable animal model that exhibits characteristics similar to patients with IND. This novel mouse model can allow the easy visualization of ENS in a time- and cost-effective way to study the pathogenesis of IND. [ABSTRACT FROM AUTHOR]

The NONO::TFE3 fusion has been described in MiT family translocation renal cell carcinomas as well as extracutaneous perivascular epithelioid cell tumors (PEComas). PEComas are known to express myogenic and melanocytic markers but SOX10 and p63 positivity has never been reported. We report two primary cutaneous tumors that morphologically and molecularly fit PEComas, both harboring the NONO::TFE3 fusion, but with an unusual immunophenotype of SOX10 and p63 positivity. One case was on an 80‐year‐old male's finger, and the other one was on a 72‐year‐old female's thigh. Both were well‐circumscribed multinodular dermal tumors composed of nests of monotonous epithelioid to spindled cells with pale to vacuolated cytoplasm, some of which were arranged around blood vessels. Both tumors were positive for SOX10, S100, and p63, focally positive for Melan‐A, and negative for myogenic markers. There are very little data regarding the molecular findings of primary cutaneous PEComas. While the NONO::TFE3 fusion has been identified in extracutaneous PEComas, it has never been reported in primary cutaneous cases. We believe these cases represent a previously undescribed subtype of cutaneous tumor which shows some immunophenotypic expression of melanocytic markers and we named these cases NONO::TFE3 fusion cutaneous epithelioid and spindle cell tumor. Further, we raise the question of whether this tumor should fall under the rubric of PEComa because of its morphology, partial expression of melanocytic markers, and the presence of the NONO::TFE3 fusion, or whether these tumors represent a separate novel class of tumors since the immunophenotypic expression of SOX10 and p63 is unusual for PEComas. [ABSTRACT FROM AUTHOR]

Demyelination is a pathological feature commonly observed in various central nervous system diseases. It is characterized by the aggregation of oligodendrocyte progenitor cells (OPCs) in the lesion area, which face difficulties in differentiating into mature oligodendrocytes (OLGs). The differentiation of OPCs requires the presence of Sox10, but its expression decreases under pathological conditions. Therefore, we propose a therapeutic strategy to regulate OPCs differentiation and achieve myelin repair by endogenously loading Sox10 into exosomes. To accomplish this, we generated a lentivirus-armed Sox10 that could anchor to the inner surface of the exosome membrane. We then infected HEK293 cells to obtain exosomes with high expression of Sox10 (exosomes-Sox10, ExoSs). In vitro, experiments confirmed that both Exos and ExoSs can be uptaken by OPCs, but only ExoSs exhibit a pro-differentiation effect on OPCs. In vivo, we administered PBS, Exos, and ExoSs to cuprizone-induced demyelinating mice. The results demonstrated that ExoSs can regulate the differentiation of PDGFRα+ OPCs into APC+ OLGs and reduce myelin damage in the corpus callosum region of the mouse brain compared to other groups. Further testing suggests that Sox10 may have a reparative effect on the myelin sheath by enhancing the expression of MBP, possibly facilitated by the exosome delivery of the protein into the lesion. This endogenously loaded technology holds promise as a strategy for protein-based drugs in the treatment of demyelinating diseases.

Spiral ganglion neurons (SGNs) in the mammalian cochleae are essential for the delivery of acoustic information, and damage to SGNs can lead to permanent sensorineural hearing loss as SGNs are not capable of regeneration. Cochlear glial cells (GCs) might be a potential source for SGN regeneration, but the neuronal differentiation ability of GCs is limited and its properties are not clear yet. Here, we characterized the cochlear Sox10-positive (Sox10+) GCs as a neural progenitor population and developed a basement membrane extract-based three-dimensional (BME-3D) culture system to promote its neuronal generation capacity in vitro. Firstly, the purified Sox10+ GCs, isolated from Sox10-creER/tdTomato mice via flow cytometry, were able to form neurospheres after being cultured in the traditional suspension culture system, while significantly more neurospheres were found and the expression of stem cell-related genes was upregulated in the BME-3D culture group. Next, the BME-3D culture system promoted the neuronal differentiation ability of Sox10+ GCs, as evidenced by the increased number, neurite outgrowth, area of growth cones, and synapse density as well as the promoted excitability of newly induced neurons. Notably, the BME-3D culture system also intensified the reinnervation of newly generated neurons with HCs and protected the neurospheres and derived-neurons against cisplatin-induced damage. Finally, transcriptome sequencing analysis was performed to identify the characteristics of the differentiated neurons. These findings suggest that the BME-3D culture system considerably promotes the proliferation capacity and neuronal differentiation efficiency of Sox10+ GCs in vitro, thus providing a possible strategy for the SGN regeneration study.

Neural crest (NC) cells are a dynamic population of embryonic stem cells that create various adult tissues in vertebrate species including craniofacial bone and cartilage and the peripheral and enteric nervous systems. NC development is thought to be a conserved and complex process that is controlled by a tightly-regulated gene regulatory network (GRN) of morphogens, transcription factors, and cell adhesion proteins. While multiple studies have characterized the expression of several GRN factors in single species, a comprehensive protein analysis that directly compares expression across development is lacking. To address this lack in information, we used three closely related avian models, Gallus gallus (chicken), Coturnix japonica (Japanese quail), and Pavo cristatus (Indian peafowl), to compare the localization and timing of four GRN transcription factors, PAX7, SNAI2, SOX9, and SOX10, from the onset of neurulation to migration. While the spatial expression of these factors is largely conserved, we find that quail NC cells express SNAI2, SOX9, and SOX10 proteins at the equivalent of earlier developmental stages than chick and peafowl. In addition, quail NC cells migrate farther and more rapidly than the larger organisms. These data suggest that despite a conservation of NC GRN players, differences in the timing of NC development between species remain a significant frontier to be explored with functional studies.

The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the Tle4 gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.

Introduction. Cutaneous melanoma is one of the most aggressive malignant tumors, and its nodular form with vertical growth is characterized by unfavorable prognosis. However, in the recent years due to advances in basic oncology, a breakthrough in drug therapy of this pathology was made. To a great extent, it is linked to implementation of new therapy with checkpoint inhibitors. The best and longest response rates of cutaneous melanoma to this treatment were achieved compared to other oncological diseases. This fact can be explained by immunogenicity of cutaneous melanoma, high mutational load, as well as features of its tumor microenvironment, where in most cases high infiltration by immunocompetent cell is observed. However, immune cells vary by their composition and functions. Some of them can even promote tumor growth. Therefore, study of cell composition, degree and distribution of immune infiltration in the tumor can help identify potential factors of favorable and unfavorable prognosis for cutaneous melanoma which is important in clinical practice.Aim. To determine the frequency of CD3+-, CD4+-, CD8+-T-lymphocytes, CD163, BCL6 and SOX10 expression in patients with primary nodular cutaneous melanoma, as well as correlation of these markers with each other and standard morphological parameters for this non-epithelial malignant tumor.Materials and methods. In the study, the expression frequency of CD3+-, CD4+-, CD8+-T-lymphocytes, CD163, BCL6 and SOX10 in the postoperative material of 20 patients with true primary nodular cutaneous melanoma was measured using immunohistological analysis. The correlation of these markers with each other and standard morphological parameters was determined.Results. In most cases of nodular cutaneous melanoma, moderate and marked lymphocytic (immune) infiltration (grade II–III) was observed with no correlation with Breslow tumor thickness. Study of the ratio between CD4-positive T helpers and CD8-positive cytotoxic T lymphocytes in the tumor microenvironment showed that the number of the latter increased the higher was the degree of immune infiltrate. Markedness of macrophage infiltration directly correlated with markedness of lymphocytic infiltration. BCL6 expression in lymphocytes was observed in all cases of infiltration.Conclusion. Immune infiltrate in nodular cutaneous melanoma is a multicomponent, dynamic microenvironment containing both antitumor and tumor-promoting components with balance shifting to one or other side. Their qualitative, quantitative and, possibly, topographic ratios in the primary lesion of cutaneous melanoma affect the effectiveness of drugs and disease prognosis. Knowledge on the predominance of components negatively affecting tumor growth in the primary lesion can help an oncologist in selection of correct treatment tactics and disease observation.

Malignant melanoma of the rectum is an exceedingly rare type of cancer with an aggressive presentation, comprising up to 4% of all anorectal cancers. Presentation of this cancer tends to occur in individuals in their late 80s, with nonspecific symptoms such as anal pain or rectal bleeding. Diagnosing rectal melanoma, especially in early stages, is difficult due to its amelanotic presentation and lack of pigmentation, which results in poor remission rates and prognosis. Furthermore, surgical treatment is difficult as these types of malignant melanomas tend to spread along submucosal planes; thus, complete resections are impractical, especially if caught later. In this case report, we present the radiological and pathological features as seen in a 76-year-old man diagnosed with rectal melanoma. Based on his presentation of a heterogeneous bulky anorectal mass with extensive local invasion, initial impressions were colorectal carcinoma. However, surgical pathology found the mass to be a c-KIT+ melanoma, with positive SOX10, Melan-A, HMB-45, and CD117 biomarkers. While the patient was treated with imatinib, the melanoma was too widespread and aggressive, leading to progression and ultimately death.

Background: The diagnostic utility of SRY-box transcription factor 10 (SOX10) expression in basal-like breast cancer (BLBC) has been reported previously. However, the effect of SOX10 on the malignancy of BLBC cells and the underlying molecular mechanisms remain unelucidated. Here, we investigate the regulatory mechanisms and roles of SOX10 in BLBC progression. Methods: Sequencing data from patients with BLBC were extracted from the Cancer Genome Atlas database to determine the transcriptomic levels of SOX10 across breast cancer subtypes. Subsequently, the bioinformatics relevance of SOX10 in BLBC was investigated. Immunohistochemical assays were used to corroborate the protein expression of SOX10 in clinicopathological specimens (human breast cancer paraffin tissues). RNA interference was used to downregulate SOX10 expression, and the efficiency of interference was evaluated using quantitative PCR. The expression levels of molecules related to the epithelial-mesenchymal transition (EMT) pathway were determined by western blotting. Various assays, such as transwell, colony formation, and flow apoptosis assays, were conducted to assess the malignancy of BLBC cells (MDA-MB-231). Results: Bioinformatics analyses revealed the differential expression of SOX10 in various breast cancer subtypes. An association between SOX10 and immune checkpoint expression was observed in BLBC. Additionally, immune correlation analysis indicated a positive relationship between SOX10 expression and effector immune cells. SOX10 was identified as a potential immunotherapeutic target. Juxtaposed with non-basal-like breast cancer (N-BLBC) and breast adenosis, immunohistochemical analysis revealed the upregulated expression of SOX10 in BLBC, indicating its potential diagnostic significance. Single-gene functional enrichment analysis indicated that SOX10 is associated with EMT and the tumor inflammatory index. Experimental outcomes from cellular assays suggested that the downregulation of SOX10 inhibited multiple malignancy-associated behaviors in MDA-MB-231 cells, specifically affecting the EMT process, migration, invasion, proliferation, clone formation, and anti-apoptotic activities. Conclusions: We concluded that SOX10 contributes to the malignancy of BLBC cells by modulating the EMT pathway. Moreover, we observed a notable correlation between SOX10 expression and immune responses, indicating the potential significance of SOX10 in immunotherapy.

The visual appearance of humans is derived significantly from our skin and hair color. While melanin from epidermal melanocytes protects our skin from the damaging effects of ultraviolet radiation, the biological value of pigmentation in the hair follicle, particularly on the scalp, is less clear. In this study, we explore the heterogeneity of pigment cells in the human scalp anagen hair follicle bulb, a site conventionally viewed to be focused solely on pigment production for transfer to the hair shaft. Using c-KIT/CD117 microbeads, we isolated bulbar c-KIT-positive and c-KIT-negative melanocytes. While both subpopulations expressed MITF, only the c-KIT-positive fraction expressed SOX10. We further localized bulbar melanocyte subpopulations (expressing c-KIT, SOX10, MITF, and DCT) that exhibited distinct/variable expression of downstream differentiation-associated melanosome markers (e.g., gp100 and Melan-A). The localization of a second 'immature' SOX10 negative melanocyte population, which was c-KIT/MITF double-positive, was identified outside of the melanogenic zone in the most peripheral/proximal matrix. This study describes an approach to purifying human scalp anagen hair bulb melanocytes, allowing us to identify unexpected levels of melanocyte heterogeneity. The function of the more immature melanocytes in this part of the hair follicle remains to be elucidated. Could they be in-transit migratory cells ultimately destined to synthesize melanin, or could they contribute to the hair follicle in non-melanogenic ways? [ABSTRACT FROM AUTHOR]

Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic applications. Objective: The objective of this study was the identification of key genes and inhibitory drugs related to the cell proliferation and invasion of ameloblastoma using bioinformatic analysis. Methods: The H10KA_07_38 gene profile database was analyzed by Rstudio and ShinyGO Gene Ontology enrichment. String, Cytoscape-MCODE, and Kaplan–Meier plots were generated, which were subsequently validated by RT-qPCR relative expression and immunoexpression analyses. To propose specific inhibitory drugs, a bioinformatic search using Drug Gene Budger and DrugBank was performed. Results: A total of 204 significantly upregulated genes were identified. Gene ontology enrichment analysis identified four pathways related to cell proliferation and cell invasion. A total of 37 genes were involved in these pathways, and 11 genes showed an MCODE score of ≥0.4; however, only SLC6A3, SOX10, and LRP5 were negatively associated with overall survival (HR = 1.49 (p = 0.0072), HR = 1.55 (p = 0.0018), and HR = 1.38 (p = 0.025), respectively). The RT-qPCR results confirmed the significant differences in expression, with overexpression of >2 for SLC6A3 and SOX10. The immunoexpression analysis indicated positive LRP5 and SLC6A3 expression. The inhibitory drugs bioinformatically obtained for the above three genes were parthenolide and vorinostat. Conclusions: We identify LRP5, SLC6A3, and SOX10 as potentially important genes related to cell proliferation and invasion in the pathogenesis of ameloblastomas, along with both parthenolide and vorinostat as inhibitory drugs that could be further investigated for the development of novel therapeutic approaches against ameloblastoma. [ABSTRACT FROM AUTHOR]

Objectives Granular cell tumor (GCT) commonly presents in the subcutaneous tissue and head and neck region, and it is uncommon in the gastrointestinal tract. Experience with esophageal GCTs in the pediatric population is limited, with only 7 cases reported in the literature, 3 with eosinophilic esophagitis (EoE). Methods Case information from 11 pediatric patients with GCTs of the esophagus was retrieved. H&E and immunohistochemical slides were reviewed with clinical, endoscopic, and follow-up data from all patients. Results In total, 7 male and 4 female patients were included, with ages ranging from 3 to 14 years. Indications for esophagogastroduodenoscopy (EGD) included EoE (n = 3), follow-up for Crohn disease, and other nonspecific complaints. Endoscopically, all patients had a single submucosal, firm mass protruding into the lumen, with normal overlying mucosa. The nodules were removed endoscopically in multiple fragments in all cases. Histologically, the tumors showed sheets and trabeculae of cells containing bland nuclei, inconspicuous nucleoli, and abundant pink granular cytoplasm without atypical features. All tumors were immunoreactive for S100, CD68, and SOX10. Follow-up showed that all patients were disease-free (median, 2 years). Conclusions We report the largest series of pediatric esophageal GCTs with coincidental association with EoE. These EGD findings are characteristic, and removal by biopsy is both diagnostic and therapeutic. [ABSTRACT FROM AUTHOR]

Malignant melanoma of the rectum is an exceedingly rare type of cancer with an aggressive presentation, comprising up to 4% of all anorectal cancers. Presentation of this cancer tends to occur in individuals in their late 80s, with nonspecific symptoms such as anal pain or rectal bleeding. Diagnosing rectal melanoma, especially in early stages, is difficult due to its amelanotic presentation and lack of pigmentation, which results in poor remission rates and prognosis. Furthermore, surgical treatment is difficult as these types of malignant melanomas tend to spread along submucosal planes; thus, complete resections are impractical, especially if caught later. In this case report, we present the radiological and pathological features as seen in a 76-year-old man diagnosed with rectal melanoma. Based on his presentation of a heterogeneous bulky anorectal mass with extensive local invasion, initial impressions were colorectal carcinoma. However, surgical pathology found the mass to be a c-KIT+ melanoma, with positive SOX10, Melan-A, HMB-45, and CD117 biomarkers. While the patient was treated with imatinib, the melanoma was too widespread and aggressive, leading to progression and ultimately death. [ABSTRACT FROM AUTHOR]

Waardenburg syndrome is an autosomal dominant inherited syndromic hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. The aim of this study was to analyze the clinical phenotypes and genetic variants of a Chinese boy with Waardenburg syndrome type 2 and to explore the possible molecular pathogenesis of Waardenburg syndrome type 2. Clinical, audiological, and ophthalmologic evaluations were performed on the proband. Clinical data from the principal members in the proband's family were collected through questionnaires. Genetic analysis was conducted, including targeted next-generation sequencing of 144 known deafness genes, Sanger sequencing, and bioinformatic analysis. Waardenburg syndrome type 2was diagnosed in a 4-year-old boy according to the Waardenburg Syndrome Consortium Criteria. The novel missense mutation c.426G>T (p.Trp142Cys) was identified in SOX10 in the proband but was absent in his parents and the controls. A de novo missense mutation in SOX10 was the genetic cause of Waardenburg syndrome type 2 in the proband, which was useful for the molecular diagnosis of Waardenburg syndrome type 2. [ABSTRACT FROM AUTHOR]

Odontogenic tumors show considerable morphologic heterogeneity and at times the diagnosis can be challenging. Ameloblastoma, the most common odontogenic tumor, can have morphologic similarity to some salivary gland tumors and therefore we sought to identify biomarkers that might aid in the diagnosis by performing transcriptome wide gene expression profiling of 80 odontogenic and salivary gland neoplasms. These data identified the FOXP1/SOX10 expression profile as characteristic of many odontogenic tumors including ameloblastoma but largely absent in salivary gland tumors. We then assessed 173 salivary gland tumors and 108 odontogenic tumors by immunohistochemistry for FOXP1 and SOX10 expression and found that 34/35 (97%) cases of ameloblastomas were diffusely positive for FOXP1 but completely negative for SOX10. None of the basaloid salivary neoplasms (basal cell adenoma, adenoid cystic carcinoma, polymorphous adenocarcinoma, and myoepitheloma) demonstrated FOXP1/SOX10 expression pattern. Taken together, the results of this study suggest that the FOXP1/SOX10 immunophenotype is common in odontogenic tumors including ameloblastoma and might be useful distinguishing these from similar appearing basaloid salivary gland tumors.

Sox10 immunostaining is used for the diagnosis and margin evaluation of melanocytic lesions. Sox10 was initially thought not to stain fibrohistiocytic processes. Consequently, it was believed to reliably distinguish desmoplastic melanoma from scar. However, recent data from formalin sections suggest Sox10 is less specific than previously thought. In this report, we demonstrate that Sox10-stained Mohs sections commonly show strong, fractional staining of scar. When using Sox10 with frozen section immunohistochemistry, Mohs practitioners should recognize the potential of this marker to stain scar to avoid overdiagnosis of desmoplastic melanoma.

Introduction: Metastatic cancers are frequently detected on fine-needle aspiration (FNA) cytology, and confirmation of metastatic breast cancer often requires immunocytochemistry. Tissue provisioning for FNA specimens is important. In this study, GATA3, gross cystic disease fluid protein-15 (GCDFP15), mammaglobin (MMG), and SOX10 were performed on cell block preparations from aspirates of histologically confirmed metastatic breast cancers. The diagnostic performance of single markers and combinations of these markers were investigated with the aim to construct a tissue-efficient immunopanel. Methodology: Aspirates of metastatic breast cancer with corresponding histology and biomarker (estrogen receptor (ER), progesterone receptor (PR), HER2 and ki67) profile were retrieved. ER, GATA3, GCDFP15, MMG and SOX10 immunostains were performed on cell block sections and their expressions were assessed and compared. Results: Immunostaining was performed on a total of 115 aspirates. GATA3 showed the highest expression, followed by MMG, GCDFP15 and SOX10. Twenty-three, five and five cases expressed GATA3, MMG and SOX10 only. The five cases expressing SOX10 only were ER negative, and SOX10 expression was negatively associated with ER (p = 0.001), MMG (p = 0.001), GCDFP15 (p = 0.010) and GATA3 (p = 0.002), whereas GATA3 expression showed positive correlation with ER positivity (p < 0.001). MMG and GCDFP15 showed association with high Ki67 (p < 0.05), and no correlations were found with HER2 expression. Conclusion: In this cohort, GATA3 was the most sensitive single marker. The addition of MMG and SOX10 increases the sensitivity for detection of ER positive and ER negative breast cancers, respectively. These findings support the use of a combination of GATA3/MMG/SOX10 for confirmation of metastatic breast cancer.

Intracerebral hemorrhage (ICH) is classified as a lethal neurological injury associated with cerebrovascular disorders. Ferroptosis is a unique form of cell death and participates in ICH pathogenesis. Herein, the role of SRY-box transcription factor 10 (SOX10) in ferroptosis of hippocampal neurons after ICH was investigated. The in vitro ICH models were established by treating immortalized mouse hippocampal cell line HT-22 with Hemin. Quantitative real-time polymerase chain reaction and Western blotting revealed that the transcription factor SOX10 and microRNA (miR)-29a-3p were decreased whereas acyl-CoA synthetase longchain family member 4 (ACSL4) was increased in the ICH cell models. Subsequently, the assays of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, the commercial kits, and fluorescent labeling revealed that SOX10 overexpression improved cell viability, decreased the amount of reactive oxygen species (ROS) and Fe2þ, and increased the amount of glutathione (GSH) and glutathione peroxidase 4 (GPX4) in ICH models. Thereafter, chromatin immunoprecipitation and dual-luciferase assays showed that SOX10 binding to the miR-29a-3p promoter region increased miR-29a-3p expression, and miR-29a-3p targeted and limited ACSL4 transcription. Rescue experiments showed that miR-29a-3p downregulation or ACSL4 overexpression expedited ferroptosis of Hemin-treated HT-22 cells. Taken together, SOX10 contributed to ferroptosis of hippocampal neurons after ICH via increasing miR-29a-3p to limit ACSL4 transcription. NEW & NOTEWORTHY SOX10 promotes the expression of Mir-29a-3p by binding to the promoter region of Mir-29a-3p, thereby targeting the expression of ACSL4 and inhibiting the iron death of hippocampal neuronal cells in mice with ICH. [ABSTRACT FROM AUTHOR]

The COMMD (copper metabolism MURR1 domain containing) family includes ten structurally conserved proteins (COMMD1 to COMMD10) in eukaryotic multicellular organisms that are involved in a diverse array of cellular and physiological processes, including endosomal trafficking, copper homeostasis, and cholesterol metabolism, among others. To understand the role of COMMD10 in embryonic development, we used Commd10Tg(Vav1-icre)A2Kio/J mice, where the Vav1-cre transgene is integrated into an intron of the Commd10 gene, creating a functional knockout of Commd10 in homozygous mice. Breeding heterozygous mice produced no COMMD10-deficient (Commd10Null) offspring, suggesting that COMMD10 is required for embryogenesis. Analysis of Commd10Null embryos demonstrated that they displayed stalled development by embryonic day 8.5 (E8.5). Transcriptome analysis revealed that numerous neural crest-specific gene markers had lower expression in mutant versus wild-type (WT) embryos. Specifically, Commd10Null embryos displayed significantly lower expression levels of a number of transcription factors, including a major regulator of the neural crest, Sox10. Moreover, several cytokines/growth factors involved in early embryonic neurogenesis were also lower in mutant embryos. On the other hand, Commd10Null embryos demonstrated higher expression of genes involved in tissue remodeling and regression processes. Taken together, our findings show that Commd10Null embryos die by day E8.5 due to COMMD10-dependent neural crest failure, revealing a new and critical role for COMMD10 in neural development. [ABSTRACT FROM AUTHOR]

Stratifying breast cancer into specific molecular or histologic subtypes aids in therapeutic decision-making and predicting outcomes; however, these subtypes may not be as distinct as previously thought. Patients with luminal-like, estrogen receptor (ER)-expressing tumors have better prognosis than patients with more aggressive, triple-negative or basal-like tumors. There is, however, a subset of luminal-like tumors that express lower levels of ER, which exhibit more basal-like features. We have found that breast tumors expressing lower levels of ER, traditionally considered to be luminal-like, represent a distinct subset of breast cancer characterized by the emergence of basal-like features. Lineage tracing of low-ER tumors in the MMTV-PyMT mouse mammary tumor model revealed that basal marker-expressing cells arose from normal luminal epithelial cells, suggesting that luminal-to-basal plasticity is responsible for the evolution and emergence of basal-like characteristics. This plasticity allows tumor cells to gain a new lumino-basal phenotype, thus leading to intratumoral lumino-basal heterogeneity. Single-cell RNA sequencing revealed SOX10 as a potential driver for this plasticity, which is known among breast tumors to be almost exclusively expressed in triple-negative breast cancer (TNBC) and was also found to be highly expressed in low-ER tumors. These findings suggest that basal-like tumors may result from the evolutionary progression of luminal tumors with low ER expression. [ABSTRACT FROM AUTHOR]