UNASSIGNED: Various stemness markers (SOX2, OCT4, and NANOG) have been studied in odontogenic cysts and tumors. However, studies on SALL4 having similar properties of stemness has not been documented. Additionally, insight into fascin as a migratory molecule is less explored. In this study, the expression of SALL4 and fascin were evaluated in ameloblastoma, adenomatoid odontogenic tumor (AOT), odontogenic keratocyst (OKC), dentigerous cyst (DC), radicular cyst (RC), and calcifying odontogenic cyst (COC).
UNASSIGNED: Semi-quantitative analysis of fascin and SALL4 immuno-positive cells was done in a total of 40 cases of ameloblastoma (11 plexiform, 12 follicular, 12 unicystic, and 5 desmoplastic) variants, 6 cases of AOT, 15 each of OKC, DC, RC and 5 of COC. Chi-square test was applied to evaluate the association between SALL4 and fascin expression in odontogenic cysts and tumors.
UNASSIGNED: Fascin immunopositivity was observed in peripheral ameloblast-like cells, and weak or absent in stellate reticulum-like cells. A moderate to weak immune-reactivity to SALL4 was observed in the cytoplasm of ameloblastoma, epithelial cells of dentigerous and radicular cysts, having a marked inflammatory infiltrate, which is an interesting observation. COC and AOT had negative to weak expressions. No recurrence has been reported.
UNASSIGNED: Expression of fascin in ameloblastomas elucidate their role in motility and localized invasion. Its expression in less aggressive lesions like DC, COC, AOT will incite to explore the other functional properties of fascin. SALL4 expression in the cytoplasm of odontogenic cysts and tumors may represent inactive or mutant forms which requires further validation.

Rearrangement of the actin cytoskeleton is a prerequisite for carcinoma cells to develop cellular protrusions, which are required for migration, invasion, and metastasis. Fascin is a key protein involved in actin bundling and is expressed in aggressive and invasive carcinomas. Additionally, fascin appears to be involved in tubulin-binding and microtubule rearrangement. Pharmacophoric-based in silico screening was performed to identify compounds with better fascin inhibitory properties than migrastatin, a gold-standard fascin inhibitor. We hypothesized that monastrol displays anti-migratory and anti-invasive properties via fascin blocking in colorectal cancer cell lines. Biophysical (thermofluor and ligand titration followed by fluorescence spectroscopy), biochemical (NMR), and cellular assays (MTT, invasion of human tissue), as well as animal model studies (zebrafish invasion) were performed to characterize the inhibitory effect of monastrol on fascin activity. In silico analysis revealed that monastrol is a potential fascin-binding compound. Biophysical and biochemical assays demonstrated that monastrol binds to fascin and interferes with its actin-bundling activity. Cell culture studies, including a 3D human myoma disc model, showed that monastrol inhibited fascin-driven cytoplasmic protrusions as well as invasion. In silico, confocal microscopy, and immunoprecipitation assays demonstrated that monastrol disrupted fascin-tubulin interactions. These anti-invasive effects were confirmed in vivo. In silico confocal microscopy and immunoprecipitation assays were carried out to test whether monastrol disrupted the fascin-tubulin interaction. This study reports, for the first time, the in vitro and in vivo anti-invasive properties of monastrol in colorectal tumor cells. The number and types of interactions suggest potential binding of monastrol across actin and tubulin sites on fascin, which could be valuable for the development of antitumor therapies.

Laryngeal squamous cell carcinoma (LSCC) is a common malignant tumor with a poor prognosis. Fascin actin‑bundling protein 1 (FSCN1) has been reported to play a crucial role in the development and progression of LSCC; however, the underlying molecular mechanisms remain unknown. Herein, a whole transcriptome microarray analysis was performed to screen for differentially expressed genes (DEGs) in cells in which FSCN1 was knocked down. A total of 462 up and 601 downregulated mRNA transcripts were identified. Functional annotation analysis revealed that these DEGs were involved in multiple biological functions, such as transcriptional regulation, response to radiation, focal adhesion, extracellular matrix‑receptor interaction, steroid biosynthesis and others. Through co‑expression and protein‑protein interaction analysis, FSCN1 was linked to novel functions, including defense response to virus and steroid biosynthesis. Furthermore, crosstalk analysis with FSCN1‑interacting proteins revealed seven DEGs, identified as FSCN1‑interacting partners, in LSCC cells, three of which were selected for further validation. Co‑immunoprecipitation validation confirmed that FSCN1 interacted with prostaglandin reductase 1 and 24‑dehydrocholesterol reductase (DHCR24). Of note, DHCR24 is a key enzyme involved in cholesterol biosynthesis, and its overexpression promotes the proliferation and migration of LSCC cells. These findings suggest that DHCR24 is a novel molecule associated with FSCN1 in LSCC, and that the FSCN1‑DHCR24 interaction may promote LSCC progression by regulating cholesterol metabolism‑related signaling pathways.

Fascin actin-bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F-actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin-mediated F-actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD-dependent protein deacetylase sirtuin (SIRT) 7-mediated deacetylation of Fascin-K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin-K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin-K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP-G2-044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP-G2-044 may be more suitable for patients with low levels of Fascin-K41 acetylation, but not suitable for patients with high levels of Fascin-K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Fascin crosslinks actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during metastasis, and fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-electron microscopy, cryo-electron tomography coupled with custom denoising, and computational modeling to probe fascin\'s F-actin crosslinking mechanisms across spatial scales. Our fascin crossbridge structure reveals an asymmetric F-actin binding conformation that is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis, and simulations show how structural plasticity enables fascin to bridge varied inter-filament orientations, accommodating mismatches between F-actin\'s helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncovers geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable crosslinks that limit bundle size. Collectively, this work shows how fascin harnesses fine-tuned nanoscale structural dynamics to build and regulate micron-scale F-actin bundles.

Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. β-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate β-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by β-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that β-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic β-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC.

Cancer cell migration and metastasis are the biggest problems in the treatment of cancer patients. The most aggressive breast cancer (BC) is the triple-negative type. Therefore, effective therapeutic targets that limit cell migration are sought. One such target may be fascin, as its overexpression is characteristic to triple-negative breast cancer. The high level of fascin enables the formation of protrusion and thus promotes the invasion of cancer cells. Fascin also shows co-localization or functional relationships with other proteins. These are proteins involved in the epithelial-mesenchymal transition process, vimentin, cadherins, β-catenin, and matrix metalloproteinases 2/9 (MMP-2/9). Fascin is also involved in many signaling pathways protein kinase C-δ (PKCδ), Wnt/β-catenin, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and phosphatidylinositol 3-kinase (PI3K)-Akt. Therefore, in this article, we review currently available in vitro studies and compare them with The Cancer Genome Atlas (TCGA) data analysis of BC patients to demonstrate the role of fascin in the migration and invasion of cancer cells.

Fascin (FSCN) is an actin-binding protein that serves a critical role in cell migration and invasion, contributing to tumor metastasis. However, there is little known about the function of FSCN family in kidney renal clear cell carcinoma (KIRC). The present study used the UALCAN, gene expression profiling interactive analysis, The Cancer Genome Atlas, cBioPortal, STRING and The Tumor Immune Estimation Resource databases to investigate the transcription level, genetic alteration and biological function of FSCNs in KIRC and their association with the prognosis value and immune cell infiltration in patients with KIRC. Results showed that the expression of FSCN1 and FSCN3 was markedly upregulated in patients with KIRC, while the expression of FSCN2 showed an opposite trend, which was the same as the experiments. Furthermore, the expression levels of FSCNs were associated with pathological stage, molecular subtypes and tumor grade. The expression levels of FSCNs were statistically correlated with the immune cell infiltration in KIRC. Higher expression levels of FSCN1 and FSCN3 were associated with worse overall survival (OS) and progression-free interval of patients bearing KIRC. Univariate and multivariate analysis demonstrated that FSCN2 was an independent risk factor for OS time in KIRC. Furthermore, mutations in FSCNs were significantly associated with poor OS and progression-free survival in patients with KIRC. The FSCNs were involved in pathways including focal adhesion, endocytosis, hypertrophic cardiomyopathy, regulation of actin cytoskeleton. The results indicated that FSCN2 might serve as an independent prognostic factor for OS of KIRC and that FSCN1 and FSCN3 can be used as favorable biomarkers for predicting clinical outcomes in KIRC.

Liver cancer is one of the most prevalent cancers in Japan with hepatocellular carcinoma (HCC) as the major histological subtype. Successful novel treatments for HCC have been reported; however, recurrences or metastasis may occur, which results in poor prognoses and high mortality of HCC patients. Fascin, an actin-bundling protein, regulates cell adhesion, migration, and invasion. Its overexpression positively correlates with poor prognosis of malignant tumors, and Fascin is considered as one of the tumor biomarkers and therapeutic target proteins. In this study, we attempted to reveal the relationship between Fascin and HCC using HLE, one of the human HCC cell lines. We performed the study with classical immunocytochemistry and recently developed techniques, such as wound-healing assay, spheroid cultivation, and low-vacuum scanning electron microscopy (LV-SEM). Non-Fascin-knockdown (FKD) cell spheroid had a regular spherical appearance with tight cell-cell connections, while FKD cell spheroid had an irregular shape with loose cell-cell connections. Cells of non-FKD spheroid presented fibrous protrusions on the cell surface, contrarily, cells of FKD spheroids showed bulbous-shaped protrusions. Morphological observation of FKD and non-FKD HLE spheroids were performed using LV-SEM. Our study may help to reveal the roles of Fascin in the process of HCC formation and its malignancy.

Dendritic cells (DCs) are professional antigen-presenting cells that play a crucial role in activating naive T cells through presenting antigen information, thereby influencing immunity and anti-cancer responses. Fascin, a 55-kDa actin-bundling protein, is highly expressed in mature DCs and serves as a marker protein for their identification. However, the precise role of fascin in intratumoral DCs remains poorly understood. In this review, we aim to summarize the role of fascin in both normal and intratumoral DCs. In normal DCs, fascin promotes immune effects through facilitating DC maturation and migration. Through targeting intratumoral DCs, fascin inhibitors enhance anti-tumor immune activity. These roles of fascin in different DC populations offer valuable insights for future research in immunotherapy and strategies aimed at improving cancer treatments.