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Loss and overexpression of FAT1 occurs among different cancers, with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets (i.e. sustained following transformation), predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout mice in which Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multipanel flow cytometry revealed no ostensible differences between Fat1 conditional knockout mice and normal littermates. Further functional comparisons involving colony-forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis. [ABSTRACT FROM AUTHOR]

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS). [ABSTRACT FROM AUTHOR]

Abstract Background Nephrotic syndrome (NS) is a rare complication that can occur after haematopoietic stem cell transplantation (HSCT). In patients with membranous nephropathy (MN) who have undergone allogeneic HSCT, a new antigen called protocadherin FAT1 has been identified. Our objective is to present a case series of MN patients after HSCT with a novel antigen-based stratification. Case presentations Patients who developed full-blown NS due to MN after an HSCT were enrolled in the University Hospital Centre Zagreb study. The first two patients were treated with an HSCT for acute myeloid leukaemia, and both developed NS after cessation of graft versus host disease (GVHD) prophylaxis. The first patient had reduced kidney function, while the second had completely preserved function. Kidney biopsy showed MN with only subepithelial deposits. A thorough examination revealed that there was no secondary cause of the disease. The patients achieved complete remission after undergoing immunosuppression treatment. The third patient underwent HSCT for acute lymphoblastic leukaemia. He developed both acute and chronic GVHD and also experienced avascular hip necrosis. After sixteen years, the patient developed NS with preserved kidney function. The kidney specimen showed membranous nephropathy (MN) with mesangial and subepithelial deposits. Extensive research was conducted, but no secondary cause for the MN was detected. All three cases tested negative for anti-PLA2R antibodies. Biopsy tissue samples were analysed using laser microdissection and tandem mass spectrometry of glomeruli for the detection of different specific antigens. Patients one and two tested positive for FAT1, whereas patient three tested positive for PCSK6. Conclusions MN can develop at various time intervals after HSCT. Specific antigen testing can help establish the relationship between MN and HSCT. In the future, serum testing for anti-FAT1 antibodies in HSCT patients could be significant in diagnosing FAT1-associated MN, similar to how anti-PLA2R antibodies are significant in diagnosing PLA2R-associated MN.

Background: Nephrotic syndrome (NS) is a rare complication that can occur after haematopoietic stem cell transplantation (HSCT). In patients with membranous nephropathy (MN) who have undergone allogeneic HSCT, a new antigen called protocadherin FAT1 has been identified. Our objective is to present a case series of MN patients after HSCT with a novel antigen-based stratification. Case presentations: Patients who developed full-blown NS due to MN after an HSCT were enrolled in the University Hospital Centre Zagreb study. The first two patients were treated with an HSCT for acute myeloid leukaemia, and both developed NS after cessation of graft versus host disease (GVHD) prophylaxis. The first patient had reduced kidney function, while the second had completely preserved function. Kidney biopsy showed MN with only subepithelial deposits. A thorough examination revealed that there was no secondary cause of the disease. The patients achieved complete remission after undergoing immunosuppression treatment. The third patient underwent HSCT for acute lymphoblastic leukaemia. He developed both acute and chronic GVHD and also experienced avascular hip necrosis. After sixteen years, the patient developed NS with preserved kidney function. The kidney specimen showed membranous nephropathy (MN) with mesangial and subepithelial deposits. Extensive research was conducted, but no secondary cause for the MN was detected. All three cases tested negative for anti-PLA2R antibodies. Biopsy tissue samples were analysed using laser microdissection and tandem mass spectrometry of glomeruli for the detection of different specific antigens. Patients one and two tested positive for FAT1, whereas patient three tested positive for PCSK6. Conclusions: MN can develop at various time intervals after HSCT. Specific antigen testing can help establish the relationship between MN and HSCT. In the future, serum testing for anti-FAT1 antibodies in HSCT patients could be significant in diagnosing FAT1-associated MN, similar to how anti-PLA2R antibodies are significant in diagnosing PLA2R-associated MN. [ABSTRACT FROM AUTHOR]

Breast cancer has distinct causes and molecular characteristics at premenopausal and postmenopausal ages. The age-standardized incidence rate for postmenopausal breast cancer is more than 10 times higher than in premenopausal breast cancer. Here, we showed that the expression of 10 out of 20 most frequently mutated genes in breast cancer (namely, PIK3CA, CDH1, MUC16, PTEN, FAT3, FAT1, SPEN, ARID1A, LRP1B and RUNX1) is higher in premenopausal women with breast cancer than in postmenopausal women with breast cancer. The most significant differences in the expression in terms of menopause status were observed for RUNX1 and FAT1. Furthermore, we found that the majority of these 10 genes also show ER (estrogen receptor) or PR (progesterone receptor) status-dependent expression in both premenopausal and postmenopausal breast cancer patients. Unlike what we observed in the case of ER or PR status, the expression of most of these genes does not change depending on HER2 (human epidermal growth factor receptor 2) status in both premenopausal and postmenopausal breast cancer patients. Combined, our analysis suggests that menopause status might influence the expression of most frequently mutated genes in breast cancer, and that the most of these genes whose expression differ between pre- and post-menopausal women with breast cancer also show ER or PR status-dependent expression in women with breast cancer. [ABSTRACT FROM AUTHOR]

FAT1, a substantial transmembrane protein, plays a pivotal role in cellular adhesion and cell signaling. Numerous studies have documented frequent alterations in FAT1 across various cancer types, with its aberrant expression being linked to unfavorable survival rates and tumor progression. In the present investigation, we employed bioinformatic analyses, as well as in vitro and in vivo experiments to elucidate the functional significance of FAT1 in pan-cancer, with a primary focus on lung cancer. Our findings unveiled FAT1 overexpression in diverse cancer types, including lung cancer, concomitant with its association with an unfavorable prognosis. Furthermore, FAT1 is intricately involved in immune-related pathways and demonstrates a strong correlation with the expression of immune checkpoint genes. The suppression of FAT1 in lung cancer cells results in reduced cell proliferation, migration, and invasion. These collective findings suggest that FAT1 has potential utility both as a biomarker and as a therapeutic target for lung cancer. [ABSTRACT FROM AUTHOR]

Fat (FAT atypical cadherin) and Dchs (Dachsous cadherin–related protein) in adjacent Sertoli:Sertoli, Sertoli:spermatid, and spermatid:spermatid interfaces create an important intercellular bridge whose adhesive function is in turn supported by Fjx1, a nonreceptor Ser/Thr protein kinase. This concept is derived from earlier studies of Drosophila , which has been confirmed in this and earlier reports as well. Herein, we use the approach of knockdown of Fat1 by RNAi using primary cultures of Sertoli cells that mimicked the blood–testis barrier (BTB) in vivo, and a series of coherent experiments including functional assays to monitor the Sertoli cell tight junction (TJ) permeability barrier and a functional in vitro TJ integrity assay to assess the role of Fat1 in the testis. It was shown that planar cell polarity (PCP) protein Fat1 affected Sertoli cell function through its modulation of actin and microtubule cytoskeletal function, altering their polymerization activity through the Fat1/Fjx1 complex. Furthermore, Fat1 is intimately associated with β-catenin and α-N-catenin, as well as with Prickle 1 of the Vangl1/Prickle 1 complex, another PCP core protein to support intercellular interactions to confer PCP. In summary, these findings support the notion that the Fat:Dchs and the Vangl2:Fzd PCP intercellular bridges are tightly associated with basal ES/TJ structural proteins to stabilize PCP function at the Sertoli:Sertoli, Sertoli:spermatid, and spermatid:spermatid interface to sustain spermatogenesis. [ABSTRACT FROM AUTHOR]

Glomerulocystic kidney disease (GCKD), a rare nephrocystic disorder, was the focus of this study. The FAT1 gene, comprising 27 exons, encoded a single-pass transmembrane protein with multiple biological functions. The extracellular portion of this protein consisted of 33 cadherin repeat sequences, 5 epidermal growth factor-like domains, and a G-layer associated domain. This report detailed a case of glomerular cystic disease caused by a mutation in the FAT1 gene, which was treated with the traditional Chinese medicine formula ‘Shen Jiu Fang Modified’. This formula included Astragalus, Atractylodes, Poria, Angelica, Clematis, Silkworm, Hedyotis diffusa, Hibiscus leaf, among other ingredients, and aimed to invigorate the spleen and promote diuresis, as well as to nourish the kidneys and promote blood circulation. This case demonstrated the potential of traditional Chinese medicine in addressing rare kidney diseases, offering new insights for the diagnosis and treatment of similar complex cases. [ABSTRACT FROM AUTHOR]

Background and objective Lung cancer is a leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common pathological subtype, with adenocarcinoma being the predominant type. FAT atypical cadherin 1 (FAT1) is a receptor-like protein with a high frequency of mutations in lung adenocarcinoma. The protein encoded by FAT1 plays a crucial role in processes such as cell adhesion, proliferation, and differentiation. This study aims to investigate the expression of FAT1 in lung adenocarcinoma and its relationship with immune infiltration. Methods Gene expression levels and relevant clinical information of 513 lung adenocarcinoma samples and 397 adjacent lung samples were obtained through The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data. The mRNA expression levels of the FAT1 gene in lung adenocarcinoma tissues were analyzed, along with its association with the prognosis of lung adenocarcinoma patients. Pathway enrichment analysis was conducted to explore the signaling pathways regulated by the FAT1 gene. Immunoblotting was used to detect the differential expression of FAT1 in lung epithelial cells and various lung cancer cell lines, while immunohistochemistry was employed to assess FAT1 expression in lung cancer and adjacent tissues. Results FAT1 gene mutations were identified in 14% of lung adenocarcinoma patients. TCGA database data revealed significantly higher FAT1 mRNA expression in lung adenocarcinoma tissues compared to adjacent lung tissues. Kaplan-Meier analysis indicated lower survival rates in lung adenocarcinoma patients with higher FAT gene expression. Pathway enrichment analysis suggested the involvement of FAT1 in tumor development pathways, and its expression was closely associated with immune cell infiltration. Immunohistochemical validation demonstrated significantly higher expression of FAT1 in cancer tissues compared to adjacent lung tissues. Conclusion FAT1 mRNA is highly expressed in lung adenocarcinoma tissues, and elevated FAT1 mRNA expression is associated with poor prognosis in lung adenocarcinoma patients. FAT1 may serve as a potential biomarker for lung cancer.

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies found that FAT1 was recurrently mutated and aberrantly expressed in multiple cancers, and the loss function of FAT1 promoted the formation of cancer-initiating cells in several cancers. However, in some types of cancer, FAT1 upregulation could lead to epithelial-mesenchymal transition (EMT). The role of FAT1 in cancer progression, which appears to be cancer-type-specific, is largely unknown. Methods: QRT-PCR and immunochemistry were used to verify the expression of FAT1 in non-small cell lung cancer (NSCLC). QRT-PCR and Western blot were used to detect the influence of siFAT1 knockdown on the expression of potential targets of FAT1 in NSCLC cell lines. GEPIA, KM-plotter, CAMOIP, and ROC-Plotter were used to evaluate the association between FAT1 and clinical outcomes based on expression and clinical data from TCGA and immune checkpoint inhibitors (ICI) treated cohorts. Results: We found that FAT1 upregulation was associated with the activation of TGF-β and EMT signaling pathways in NSCLC. Patients with a high FAT1 expression level tend to have a poor prognosis and hard to benefit from ICI therapy. Genes involved in TGF-β/EMT signaling pathways (SERPINE1, TGFB1/2, and POSTN) were downregulated upon knockdown of FAT1. Genomic and immunologic analysis showed that high cancer-associated fibroblast (CAF) abundance, decreased CD8+ T cells infiltration, and low TMB/TNB were correlated with the upregulation of FAT1, thus promoting an immunosuppressive tumor microenvironment (TME) which influence the effect of ICI-therapy. Conclusion: Our findings revealed the pattern of FAT1 upregulation in the TME of patients with NSCLC, and demonstrated its utility as a biomarker for unfavorable clinical outcomes, thereby providing a potential therapeutic target for NSCLC treatment.

Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune checkpoint inhibitors. The Hippo signaling pathway, originally discovered as a mechanism regulating tissue growth and organ size, transduces intracellular and extracellular signals to regulate the transcriptional co-activators YAP and TAZ. Alterations in the Hippo pathway resulting in persistent YAP and TAZ activation have emerged as major oncogenic drivers. Our analysis of the human HNSCC oncogenome revealed multiple genomic alterations impairing Hippo signaling and activating YAP and TAZ, which in turn contribute to HNSCC development. This includes mutations and deletions of the FAT1 gene (29%) and amplification of the WWTR1 (encoding TAZ, 14%) and YAP1 genes (8%), together representing one of the most genetically altered signaling mechanisms in this malignancy. Here, we discuss key elements of the mammalian Hippo pathway, detail mechanisms by which perturbations in Hippo signaling promote HNSCC initiation and progression and outline emerging strategies to target Hippo signaling vulnerabilities as part of novel multimodal precision therapies for HNSCC.

Zi-Li Huang,1,2,* Ping-Bao Zhang,1,3,* Jun-Tao Zhang,4 Feng Li,5 Ting-Ting Li,6 Xiu-Yan Huang1 1Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Radiology, Xuhui District Central Hospital of Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 5School of Materials of Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 6Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-Yan Huang, Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi Shan Road, Shanghai, People’s Republic of China, Tel/Fax +86-21-64701361, Email xyhuang1119@163.comBackground: FAT atypical cadherin 1 (FAT1) acts as a tumor suppressor or oncogene, which regulates cell adherence, proliferation, motility, and actin kinetics. FAT1 gene expression is closely related to hepatocarcinogenesis; however, the function and mechanism of FAT1 in hepatocellular carcinoma (HCC) remain unclear.Methods: Here, we screened for the FAT1, which is intimately linked to the development and progression of HCC, both in circulating tumor cells (CTCs) and tumor tissues using next generation sequencing (NGS). Immunohistochemical staining was performed to detect FAT1 protein expression. To determine the impact of FAT1 on epithelial–mesenchymal transition (EMT), migration and invasion of HCC, an in vitro transwell assay and Western blot were performed. Moreover, Gene Set Enrichment Analysis was carried out to discover the underlying mechanism. Finally, animal experiments were conducted to confirm the effects of FAT1 on HCC metastasis and tumorigenicity.Results: Our results showed that FAT1 expression was decreased in HCC tissues, while in vitro and in vivo, the FAT1 knockdown facilitated invasion, cell motility, colony formation, and proliferation. FAT1 knockdown also resulted in decreased expression of E-cadherin and markedly elevated expression of N-cadherin, vimentin, and snail. We also confirmed our hypothesis from the analysis of group differences in the CTC phenotype and lung metastasis in nude mice.Conclusion: Our findings illustrated that FAT1 played a negative regulatory role in the HCC EMT and metastasis, providing further evidence for the role played by FAT1 in the formation and progression of HCC.Keywords: hepatocellular carcinoma, FAT1, epithelial-mesenchymal transition, circulating tumor cells, metastasis

Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1's effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration. [ABSTRACT FROM AUTHOR]

The invasion of cancer cells into interstitial tissues in a cohesive unit is termed collective invasion, and it is important for the invasion and metastasis of salivary adenoid cystic carcinoma (SACC). However, the underlying mechanisms regulating SACC collective invasion are still poorly understood. Here, we found that SACC tissues exhibited remarkable FAT1 downregulation and YAP1 upregulation at the invasive front, which was closely associated with collective invasion and distant metastasis. Decreasing FAT1 expression significantly activated the YAP1 signaling pathway and promoted collective invasion. Moreover, miR-183-5p was identified as the candidate regulator of FAT1 by bioinformatic analysis and an online database algorithm. A dual luciferase reporter experiment further confirmed that miR-183-5p directly targeted the FAT1 3′-UTR to reduce FAT1 expression. Increasing or decreasing miR-183-5p expression promoted or attenuated collective invasion, which was reversed by YAP1 siRNA or FAT1 siRNA, respectively. In addition, knocking down miR-183-5p reduced tumor burden and attenuated collective invasion in vivo. Together, these results suggest that the miR-183-5p/FAT1/YAP1 signaling pathway is a critical driver of SACC collective invasion, revealing a novel therapeutic target. [Display omitted] • FAT1 downregulation and YAP1 upregulation are related to metastasis. • Multicellular and single cell methods were used to evaluate collective invasion. • miR-183-5p can directly target the FAT1 3′-UTR to activate the YAP1 signaling pathway. • Knocking down miR-183-5p prevented tumor growth and collective invasion in vivo. [ABSTRACT FROM AUTHOR]

Background: FAT atypical cadherin 1 (FAT1) is a member of the cadherin superfamily whose loss or gain is associated with the initiation and/or progression of different cancers. FAT1 overexpression has been reported in hematological malignancies. This research intended to investigate FAT1 gene expression in adult Iranian acute leukemia patients, compared to normal mobilized peripheral blood CD34+ cells. Materials and Methods: The peripheral blast (peripheral blood mononuclear cells) cells of 22 acute myeloid leukemia (AML), 14 acute lymphoid leukemia (ALL) patients, and mobilized peripheral blood CD34+ cells of 12 healthy volunteer stem cell donors were collected. Then, quantitative real-time polymerase chain reaction (qPCR) was used to compare FAT1 gene expression. Results: Overall, there were no significant differences in FAT1 expression between AML and ALL patients (p>0.2). Nonetheless, the mean expression level of FAT1 was significantly higher in leukemic patients (AML and ALL) than in normal CD34+ cells (p=0.029). Additionally, the FAT1 expression levels were significantly higher in both CD34+ and CD34- leukemic patients than in normal CD34+ cells (p=0.028). Conclusion: No significant differences were found between FAT1 expression in CD34+ and CD34- leukemic samples (p> 0.3). Thus, higher FAT1 expression was evident in ALL and AML leukemia cells but this appeared unrelated to CD34 expression. This suggests in a proportion of adult acute leukemia, FAT1 expression may prove to be a suitable target for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract FAT atypical cadherin 1 (FAT1) is among the most frequently mutated genes in many types of cancer. Its highest mutation rate is found in head and neck squamous cell carcinoma (HNSCC), in which FAT1 is the second most frequently mutated gene. Thus, FAT1 has great potential to serve as a target or prognostic biomarker in cancer treatment. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular “brake” on mitochondrial respiration and acts as a receptor for a signaling pathway regulating cell–cell contact interaction and planar cell polarity. In many cancers, loss of FAT1 function promotes epithelial-mesenchymal transition (EMT) and the formation of cancer initiation/stem-like cells. However, in some types of cancer, overexpression of FAT1 leads to EMT. The roles of FAT1 in cancer progression, which seems to be cancer-type specific, have not been clarified. To further study the function of FAT1 in cancers, this review summarizes recent relevant literature regarding this protein. In addition to phenotypic alterations due to FAT1 mutations, several signaling pathways and tumor immune systems known or proposed to be regulated by this protein are presented. The potential impact of detecting or targeting FAT1 mutations on cancer treatment is also prospectively discussed.

Background: FAT atypical cadherin 1 (FAT1) is a member of the cadherin superfamily whose loss or gain is associated with the initiation and/or progression of different cancers. FAT1 overexpression has been reported in hematological malignancies. This research intended to investigate FAT1 gene expression in adult Iranian acute leukemia patients, compared to normal mobilized peripheral blood CD34+ cells. Materials and Methods: The peripheral blast (peripheral blood mononuclear cells) cells of 22 acute myeloid leukemia (AML), 14 acute lymphoid leukemia (ALL) patients, and mobilized peripheral blood CD34+ cells of 12 healthy volunteer stem cell donors were collected. Then, quantitative real-time polymerase chain reaction (qPCR) was used to compare FAT1 gene expression. Results: Overall, there were no significant differences in FAT1 expression between AML and ALL patients (p>0.2). Nonetheless, the mean expression level of FAT1 was significantly higher in leukemic patients (AML and ALL) than in normal CD34+ cells (p=0.029). Additionally, the FAT1 expression levels were significantly higher in both CD34+ and CD34- leukemic patients than in normal CD34+ cells (p=0.028). Conclusion: No significant differences were found between FAT1 expression in CD34+ and CD34- leukemic samples (p> 0.3). Thus, higher FAT1 expression was evident in ALL and AML leukemia cells but this appeared unrelated to CD34 expression. This suggests in a proportion of adult acute leukemias, FAT1 expression may prove to be a suitable target for therapeutic strategies.

FAT atypical cadherin 1 (FAT1) is a mutant gene frequently found in human cancers and mainly accumulates at the plasma membrane of cancer cells. Emerging evidence has implicated FAT1 in the progression of gastric cancer (GC). This study intended to identify a regulatory network related to FAT1 in GC development. Upregulated expression of FAT1 was confirmed in GC tissues, and silencing FAT1 was observed to result in suppression of GC cell oncogenic phenotypes. Mechanistic investigation results demonstrated that FAT1 upregulated AP‐1 expression by phosphorylating c‐JUN and c‐FOS, whereas LINC00857 elevated the expression of FAT1 by recruiting a transcription factor TFAP2C. Functional experiments further suggested that LINC00857 enhanced the malignant biological characteristics of GC cells through TFAP2C‐mediated promotion of FAT1. More importantly, LINC00857 silencing delayed the tumor growth and blocked epithelial–mesenchymal transition in tumor‐bearing mice, which was associated with downregulated expression of TFAP2C/FAT1. To conclude, LINC00857 plays an oncogenic role in GC through regulating the TFAP2C/FAT1/AP‐1 axis. Therefore, this study contributes to extended the understanding of gastric carcinogenesis and LINC00857 may serve as a therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Primary or acquired drug resistance accounts for the failure of chemotherapy and cancer recurrence in esophageal squamous cell carcinoma (ESCC). However, the aberrant mechanisms driving drug resistance are not fully understood in ESCC. In our previous study, FAT Atypical Cadherin 1 (FAT1) was found to inhibit the epithelial–mesenchymal transition (EMT) process in ESCC. EMT plays a critical role in the development of drug resistance in multiple cancer types. Besides, it equips cancer cells with cancer stem cell (CSC)-like characters that also are associated with chemotherapy resistance. Whether FAT1 regulates the stemness or drug resistance of ESCC cells is worth being explored. Here we found that FAT1 was downregulated in ESCC spheres and negatively correlated with stemness-associated markers including ALDH1A1 and KLF4. Knocking down FAT1 enhanced the sphere-forming ability, resistance to cisplatin and drug efflux of ESCC cells. Additionally, FAT1 knockdown upregulated the expression of drug resistance-related gene ABCC3. Furtherly, we found FAT1 knockdown induced the translocation of β-catenin into nucleus and enhanced its transcriptional activity. The result of ChIP showed that β-catenin was enriched in ABCC3 promoter. Furthermore, β-catenin promoted expression of ABCC3. In conclusion, FAT1 knockdown might enhance the stemness and ABCC3-related cisplatin resistance of ESCC cells via Wnt/β-catenin signaling pathway. FAT1 and its downstream gene ABCC3 might be potential targets for overcoming chemoresistance in ESCC. [ABSTRACT FROM AUTHOR]

Abstract Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2–5% of cases. It often presents late and is unresponsive to cisplatin‐based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole‐exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle‐invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non‐SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD‐L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel‐associated (KRAB) domain‐containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited.

The FAT1 gene functions as a tumor suppressor or promoter and remains incompletely understood. We examined the clinical significance of FAT1 in head and neck squamous cell carcinoma (HNSCC) using four publicly available HNSCC cohorts and one HNSCC cohort enrolled at a tertiary medical center. We developed FAT1 signatures reflecting FAT1 mutations and mRNA expression using one cohort. Patients with HNSCC were classified into FAT1‐associated low risk (FAT1‐LR; n = 195) and FAT1‐associated high risk (FAT1‐HR; n = 371) subgroups. The five‐year overall survival and recurrence‐free survival rates were significantly lower in the FAT1‐HR subgroup than in the FAT1‐LR subgroup (P = 0.01 and 0.003, respectively). The clinical significance of FAT1 was validated using four independent cohorts. Cox proportional hazards models showed that the FAT1 signature was an independent prognostic factor for HNSCC patients. In addition, FAT1 signature was associated with the response to radiotherapy, advanced stage, and human papilloma virus (HPV) status in HNSCC patients. In conclusion, the FAT1 gene signature was associated with prognosis of HNSCC and may help to provide personalized treatments for HNSCC patients.

Genetic studies have established a connection between FAT1 (FAT atypical cadherin 1) deletion and variants and autism spectrum disorder (ASD). Here, we describe a 7‐year‐old girl who sought a neurology consultation in order to be evaluated for ASD and was found to have a de novo 4q35.2 duplication containing the FAT1 gene. Similar to other reported cases of FAT1 variants or deletion, this patient exhibits non‐syndromic ASD without facial dysmorphism or brain MRI abnormalities. We suggest also considering FAT1 duplication as a potential ASD cause. [ABSTRACT FROM AUTHOR]

The study aimed to elucidate the mutational profile of patients with newly diagnosed multiple myeloma to understand correlations of alterations with clinical outcomes. A cohort of 20 patients was enrolled, and mutational analysis was conducted using the TruSight Oncology 500 DNA Kit. Identified genetic alterations were related to clinicopathologic features and treatment outcomes. A total of 724 high-quality variants were validated. All patients harbored mutations associated with the RTK-RAS pathway, with over half having alterations in PI3 K, NOTCH, and WNT pathways. Several gene mutations were associated with specific clinical characteristics and prognostic indicators, revealing a complex interplay between genetic alterations and myeloma type, standard prognostic indicators, biochemical parameters, and renal function. Genetic alterations significantly influencing progression-free survival concerned PIK3C2B, ARID1B genes, and concomitant mutations in KMT2B, FAT1, and ARID1B. The findings underscore the potential of gene mutation-based prognostic tools in enhancing clinical decision-making and suggest that further exploration of identified genetic markers could pave the way for improved prognostic stratification and targeted therapeutic interventions in multiple myeloma., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Krzysztof Giannopoulos reports financial support was provided by National Science Center. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Vascular smooth muscle cells (VSMCs) are normally quiescent and non-migratory, regulating the contraction and relaxation of blood vessels to control the vascular tone. In response to arterial injury, these cells become active; they proliferate, secrete matrix proteins, and migrate, and thereby contribute importantly to the progression of several cardiovascular diseases. VSMC migration specifically supports atherosclerosis, restenosis after catheter-based intervention, transplant vasculopathy, and vascular remodeling during the formation of aneurysms. The atypical cadherin FAT1 is expressed robustly in activated VSMCs and promotes their migration. A positive role of FAT1 in the migration of other cell types, including neurons, fibroblasts, podocytes, and astrocyte progenitors, has also been described. In cancer biology, however, the effect of FAT1 on migration depends on the cancer type or context, as FAT1 either suppresses or enhances cancer cell migration and invasion. With this review, we describe what is known about FAT1’s effects on cell migration as well as the factors that influence FAT1-dependent migration. In VSMCs, these factors include angiotensin II, which activates FAT1 expression and cell migration, and proteins of the Atrophin family: Atrophin-1 and the short isoform of Atrophin-2, which promote VSMC migration, and the long isoform of Atrophin-2, which exerts negative effects on FAT1-dependent VSMC migration.

FAT atypical cadherin 1 (FAT1) is among the most frequently mutated genes in many types of cancer. Its highest mutation rate is found in head and neck squamous cell carcinoma (HNSCC), in which FAT1 is the second most frequently mutated gene. Thus, FAT1 has great potential to serve as a target or prognostic biomarker in cancer treatment. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular "brake" on mitochondrial respiration and acts as a receptor for a signaling pathway regulating cell–cell contact interaction and planar cell polarity. In many cancers, loss of FAT1 function promotes epithelial-mesenchymal transition (EMT) and the formation of cancer initiation/stem-like cells. However, in some types of cancer, overexpression of FAT1 leads to EMT. The roles of FAT1 in cancer progression, which seems to be cancer-type specific, have not been clarified. To further study the function of FAT1 in cancers, this review summarizes recent relevant literature regarding this protein. In addition to phenotypic alterations due to FAT1 mutations, several signaling pathways and tumor immune systems known or proposed to be regulated by this protein are presented. The potential impact of detecting or targeting FAT1 mutations on cancer treatment is also prospectively discussed. [ABSTRACT FROM AUTHOR]

STAT1 (Signal Transducer and Activator of Transcription 1), belongs to the STAT protein family, essential for cytokine signaling. It has been reported to have either context dependent oncogenic or tumor suppressor roles in different tumors. Earlier, we demonstrated that Glioblastoma multiforme (GBMs) overexpressing FAT1, an atypical cadherin, had poorer outcomes. Overexpressed FAT1 promotes pro-tumorigenic inflammation, migration/invasion by downregulating tumor suppressor gene, PDCD4. Here, we demonstrate that STAT1 is a novel mediator downstream to FAT1, in downregulating PDCD4 in GBMs. In-silico analysis of GBM databases as well as q-PCR analysis in resected GBM tumors showed positive correlation between STAT1 and FAT1 mRNA levels. Kaplan-Meier analysis showed poorer survival of GBM patients having high FAT1 and STAT1 expression. SiRNA-mediated knockdown of FAT1 decreased STAT1 and increased PDCD4 expression in glioblastoma cells (LN229 and U87MG). Knockdown of STAT1 alone resulted in increased PDCD4 expression. In silico analysis of the PDCD4 promoter revealed four putative STAT1 binding sites (Site1-Site4). ChIP assay confirmed the binding of STAT1 to site1. ChIP-PCR revealed decrease in the binding of STAT1 on the PDCD4 promoter after FAT1 knockdown. Site directed mutagenesis of Site1 resulted in increased PDCD4 luciferase activity, substantiating STAT1 mediated PDCD4 inhibition. EMSA confirmed STAT1 binding to the Site 1 sequence. STAT1 knockdown led to decreased expression of pro-inflammatory cytokines and EMT markers, and reduced migration/invasion of GBM cells. This study therefore identifies STAT1 as a novel downstream mediator of FAT1, promoting pro-tumorigenic activity in GBM, by suppressing PDCD4 expression. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have revealed that FAT atypical cadherin 1 (FAT1) plays a tumor-suppressive or oncogenic role in a context-dependent manner in various cancers. However, the functions of FAT1 are ambiguous in tumorigenesis owing to inconsistent research in oral squamous cell carcinoma (OSCC). The present study aimed at gaining an insight into the role of FAT1 in the tumor genesis and development. Methods: The expression, mutant, and survival data analyses were done using data from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database, verified with clinical samples via real-time polymerase chain reaction (qRT-PCR), Western blot (WB), and immunohistochemical (IHC) staining. OSCC cells transfected with siRNA were employed for in vitro assessment in cell proliferation, apoptosis, and migration ability in appropriate ways. The underlying mechanism was explored by RNA sequencing after FAT1 silencing. Results: Overall, FAT1 significantly increased in OSCC with a poor prognosis outcome. The in vitro experiment showed the promoting effect of FAT1 in the proliferation and migration of OSCC cells. FAT1 can also inhibit both the early and late apoptosis of OSCC cells. RNA-sequencing analysis of FAT1 silencing revealed that the cell cycle, DNA replication, and some core genes (MCM2, MCM5, CCNE1 SPC24, MYBL2, KIF2C) may be the potential mechanism in OSCC. Conclusions: FAT1 may act as an oncogene in OSCC with potential mechanism influencing the cell cycle and DNA repair. [ABSTRACT FROM AUTHOR]

Osteosarcoma is characterized by diverse genetic mutations, including single‐nucleotide variants (SNVs), which can complicate clinical outcomes of the treatment. This study identified key mutations or polymorphisms in genes that correlate with osteosarcoma prognoses. A total of 110 patients with osteosarcoma were assigned to "good" or "poor" cohorts depending on their 5‐year disease‐free survival (DFS) after surgery and chemotherapeutic treatment. We performed next‐generation sequencing analysis of tumor tissues for prognosis‐associated SNVs in 315 tumorigenesis‐related genes, followed by modeling of clinical outcomes for these patients using random forest classification via a support vector machine (SVM). Data from the Chinese Millionome Database were used to compare SNV frequency in osteosarcoma patients and healthy people. SVM screening identified 17 nonsynonymous SNVs located in 15 genes, of which rs17224367 and rs3733406 (located in MSH2 and FAT1, respectively) were strongly correlated with osteosarcoma prognosis. These results were verified in a 26‐patient validation cohort, confirming that these SNVs could be used to predict prognosis. These results demonstrated that two SNVs located in MSH2 and FAT1 are associated with prognosis of osteosarcoma patients. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Pure squamous cell carcinoma (SCC) is the most common pure variant form of bladder cancer, found in 2–5% of cases. It often presents late and is unresponsive to cisplatin‐based chemotherapy. The molecular features of these tumours have not been elucidated in detail. We carried out whole‐exome sequencing (WES), copy number, and transcriptome analysis of bladder SCC. Muscle‐invasive bladder cancer (MIBC) samples with no evidence of squamous differentiation (non‐SD) were used for comparison. To assess commonality of features with urothelial carcinoma with SD, we examined data from SD samples in The Cancer Genome Atlas (TCGA) study of MIBC. TP53 was the most commonly mutated gene in SCC (64%) followed by FAT1 (45%). Copy number analysis revealed complex changes in SCC, many differing from those in samples with SD. Gain of 5p and 7p was the most common feature, and focal regions on 5p included OSMR and RICTOR. In addition to 9p deletions, we found some samples with focal gain of 9p24 containing CD274 (PD‐L1). Loss of 4q35 containing FAT1 was found in many samples such that all but one sample analysed by WES had FAT1 mutation or deletion. Expression features included upregulation of oncostatin M receptor (OSMR), metalloproteinases, metallothioneins, keratinisation genes, extracellular matrix components, inflammatory response genes, stem cell markers, and immune response modulators. Exploration of differentially expressed transcription factors identified BNC1 and TFAP2A, a gene repressed by PPARG, as the most upregulated factors. Known urothelial differentiation factors were downregulated along with 72 Kruppel‐associated (KRAB) domain‐containing zinc finger family protein (KZFP) genes. Novel therapies are urgently needed for these tumours. In addition to upregulated expression of EGFR, which has been suggested as a therapeutic target in basal/squamous bladder cancer, we identified expression signatures that indicate upregulated OSMR and YAP/TAZ signalling. Preclinical evaluation of the effects of inhibition of these pathways alone or in combination is merited. [ABSTRACT FROM AUTHOR]

FAT atypical cadherin 1 (FAT1) promotes glioblastoma (GBM) by promoting protumorigenic inflammatory cytokine expression in tumor cells. However, tumors also have an immunosuppressive microenvironment maintained by mediators such as transforming growth factor (TGF)-β cytokines. Here, we have studied the role of FAT1 in tumor immune suppression. Our preliminary TIMER2.0 analysis of The Cancer Genome Atlas (TCGA) database revealed an inverse correlation of FAT1 expression with infiltration of tumor-inhibiting immune cells (such as monocytes and T cells) and a positive correlation with tumor-promoting immune cells [such as myeloid-derived suppressor cells (MDSCs)] in various cancers. We have analyzed the role of FAT1 in modulating the expression of TGF-β1/2 in resected human gliomas, primary glioma cultures, and other cancer cell lines (U87MG, HepG2, Panc-1, and HeLa). Positive correlations of gene expression of FAT1 and TGF-β1/2 were observed in various cancers in TCGA, Glioma Longitudinal Analysis Consortium (GLASS), and Chinese Glioma Genome Atlas (CGGA) databases. Positive expression correlations of FAT1 were also found with TGF-β1/2 and Serpine1 (downstream target) in fresh-frozen GBM samples using q-PCR. siRNA-mediated FAT1 knockdown in cancer cell lines and in primary cultures led to decreased TGF-β1/2 expression/secretion as assessed by q-PCR, Western blotting, and ELISA. There was increased chemotaxis (transmigration) of THP-1 monocytes toward siFAT1-transfected tumor cell supernatant as a consequence of decreased TGF-β1/2 secretion. Reduced TGF-β1 expression was also observed in THP-1 cultured in conditioned media from FAT1-depleted glioma cells, thus contributing to immune suppression. In U87MG cells, decreased TGF-β1 upon FAT1 knockdown was mediated by miR-663a, a known modulator. FAT1 expression was also observed to correlate positively with the expression of surrogate markers of MDSCs [programmed death ligand-1 (PD-L1), PD-L2, and interleukin (IL)-10] in glioma tumors, suggesting a potential role of FAT1 in MDSC-mediated immunosuppression. Hence, our findings elaborate contributions of FAT1 to immune evasion, where FAT1 enables an immunosuppressive microenvironment in GBM and other cancers via TGF-β1/2.

ObjectivePrevious studies have revealed that FAT atypical cadherin 1 (FAT1) plays a tumor-suppressive or oncogenic role in a context-dependent manner in various cancers. However, the functions of FAT1 are ambiguous in tumorigenesis owing to inconsistent research in oral squamous cell carcinoma (OSCC). The present study aimed at gaining an insight into the role of FAT1 in the tumor genesis and development.MethodsThe expression, mutant, and survival data analyses were done using data from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database, verified with clinical samples via real-time polymerase chain reaction (qRT-PCR), Western blot (WB), and immunohistochemical (IHC) staining. OSCC cells transfected with siRNA were employed for in vitro assessment in cell proliferation, apoptosis, and migration ability in appropriate ways. The underlying mechanism was explored by RNA sequencing after FAT1 silencing.ResultsOverall, FAT1 significantly increased in OSCC with a poor prognosis outcome. The in vitro experiment showed the promoting effect of FAT1 in the proliferation and migration of OSCC cells. FAT1 can also inhibit both the early and late apoptosis of OSCC cells. RNA-sequencing analysis of FAT1 silencing revealed that the cell cycle, DNA replication, and some core genes (MCM2, MCM5, CCNE1 SPC24, MYBL2, KIF2C) may be the potential mechanism in OSCC.ConclusionsFAT1 may act as an oncogene in OSCC with potential mechanism influencing the cell cycle and DNA repair.

Smooth muscle cells contribute to cardiovascular disease, the leading cause of death worldwide. The capacity of these cells to undergo phenotypic switching in mature arteries of the systemic circulation underlies their pathogenic role in atherosclerosis and restenosis, among other vascular diseases. Growth factors and cytokines, extracellular matrix components, regulation of gene expression, neuronal influences, and mechanical forces contribute to smooth muscle cell phenotypic switching. Comparatively little is known about cell metabolism in this process. Studies of cancer and endothelial cell biology have highlighted the importance of cellular metabolic processes for phenotypic transitions that accompany tumor growth and angiogenesis. However, the understanding of cell metabolism during smooth muscle cell phenotypic modulation is incipient. Studies of the atypical cadherin FAT1, which is strongly upregulated in smooth muscle cells in response to arterial injury, suggest that it has important and distinctive functions in this context, mediating control of both smooth muscle cell mitochondrial metabolism and cell proliferation. Here we review the progress made in understanding how FAT1 affects the smooth muscle cell phenotype, highlighting the significance of FAT1 as a processed protein and unexpected regulator of mitochondrial respiration. These mechanisms suggest how a transmembrane protein may relay signals from the extracellular milieu to mitochondria to control metabolic activity during smooth muscle cell phenotypic switching.

It is critical to distinguish the rare neoplasm of mucin-producing urothelial-type adenocarcinoma of the prostate (MPUAP) from either prostate origin or metastatic adenocarcinoma. This is mainly because they have different tumor staging, clinical behavior and treatment plans. In the current study, we try to fulfill the lack of knowledge in this field. There were totally 24 MPUAP cases including previous reported 23 cases and adding one new MPUAP case in the current study. We performed IHC and 78 genes panel analysis in two cases of ours. Most of the cases had urinary obstruction symptoms and normal PSA level. Pathological features showed dissection of the stroma by mucin pools and glands lined by pseudostratified columnar mucinous epithelium with varying degrees of cytological atypia. The IHC results showed positive for CK20, CEA, CDX-2, β-catenin, p53, MUC2 and MUC5AC, negative for PSA, AMACR, GATA3, MUC6, AR and NKX3.1 and variable expression for HMWCK and CK7. Genetic analysis revealed concurrent mutations of FAT1 (c.10001 T>C) and HNF1A in both cases. The similar morphology features of MPUAP and colorectal adenocarcinoma were seen. Membranous staining pattern of β-catenin and genetic mutation of FAT1 and HNF1A are two distinct features in MPUAP.

Abstract Background Overexpression of FAT1 gene and its oncogenic effects have been reported in several cancers. Previously, we have documented upregulation of FAT1 gene in glioblastoma (GBM) tumors which was found to increase the expression of proinflammatory markers, HIF-1α, stemness genes and EMT markers in glioma cells. Here, we reveal NFкB (RelA)/RelA/p65 as the transcriptional regulator of FAT1 gene in GBM cells. Methods In-silico analysis of FAT1 gene promoter was performed using online bioinformatics tool Promo alggen (Transfac 8.3) to identify putative transcription factor(s) binding motifs. A 4.0 kb FAT1 promoter (− 3220 bp to + 848 bp w.r.t. TSS + 1) was cloned into promoter less pGL3Basic reporter vector. Characterization of FAT1 promoter for transcriptional regulation was performed by in-vitro functional assays using promoter deletion constructs, site directed mutagenesis and ChIP in GBM cells. Results Expression levels of NFкB (RelA) and FAT1 were found to be increased and positively correlated in GBM tumors (n = 16), REMBRANDT GBM-database (n = 214) and TCGA GBM-database (n = 153). In addition to glioma, positive correlation between NFкB (RelA) and FAT1 expression was also observed in other tumors like pancreatic, hepatocellular, lung and stomach cancers (data extracted from TCGA tumor data). A 4.0 kb FAT1-promoter-construct [− 3220 bp/+ 848 bp, transcription start site (TSS) + 1, having 17 NFкB (RelA) motifs] showed high FAT1 promoter luciferase-activity in GBM cells (U87MG/A172/U373MG). FAT1 promoter deletion-construct pGL3F1 [− 200 bp/+ 848 bp, with 3-NFкB (RelA)-motifs] showed the highest promoter activity. Exposure of GBM cells to known NFкB (RelA)-activators [severe-hypoxia/TNF-α/ectopic-NFкB (RelA) + IKBK vectors] led to increased pGL3F1-promoter activity and increased endogenous-FAT1 expression. Conversely, siRNA-mediated NFкB (RelA) knockdown led to decreased pGL3F1-promoter activity and decreased endogenous-FAT1 expression. Deletion of NFкB (RelA)-motif at − 90 bp/− 80 bp [pGL3F1δ1-construct] showed significant decrease in promoter activity. Site directed mutagenesis at -90 bp/− 80 bp and ChIP assay for endogenous-NFкB (RelA) confirmed the importance of this motif in FAT1 expression regulation. Significant reduction in the migration, invasion as well as colony forming capacity of the U87MG glioma cells was observed on siRNA-mediated knockdown of NFкB (RelA). Conclusion Since FAT1 and NFкB (RelA) are independently known to promote pro-tumorigenic inflammation and upregulate the expression of HIF-1α/EMT/stemness in tumors, targeting the NFкB (RelA)-FAT1 axis may attenuate an important tumor-promoting pathway in GBM. This may also be applicable to other tumors.

Objective To explore the mechanism of miR-223-3p regulating the occurrence and development of liver cancer cells by targeting FAT1 gene. Methods Bioinformatics analysis was used to analyze the differentially expressed genes in liver cancer tissue chips. Forty-eight cases of liver cancer tissues and corresponding adjacent tissues were selected, and qRT-PCR was used to detect the expression of miR-223-3p and FAT1mRNA in tissues. Wound healing assay was used to detect the migration ability of liver cancer cells. Transwell assay was used to detect cells invasion ability. Dual-luciferase assay was used to detect the targeting relationship between miR-223-3p and FAT1. Western blot was used to detect the protein expression of EMT-related markers, E-cadherin and Vimentin. Results FAT1 was highly expressed in liver cancer tissues and cells, while miR-223-3p was lowly expressed. Silencing FAT1 could inhibite the proliferation, migration, invasion and EMT of liver cancer cells. miR-223-3p targeted down-regulated the expression of FAT1, and inhibited the proliferation, migration, invasion and EMT of liver cancer cells by targeting FAT1. Conclusion miR-223-3p regulates the occurrence and development of liver cancer cells by targeted down-regulating the expression of FAT1.

The suppressive roles of Fat1 have been widely revealed in various tumors. However, its effects on the tumor‐initiating ability of nonsmall cell lung cancer (NSCLC) cells have never been elucidated. Currently, we identified that a higher level of Fat1 mRNA expression predicted a longer overall survival and first‐progression survival of lung cancer patients, especially in adenocarcinoma patients. In addition, Fat1 mRNA exhibited a lower level in lung cancer tissues relative to that in normal tissues. Functionally, we focused on the effects of Fat1 on the tumor‐initiating ability of NSCLC cells and we found that Fat1 overexpression decreased the expression of tumor‐initiating markers. Furthermore, overexpression of Fat1 reduced ALDH1 activity and sphere‐formation ability of NSCLC cells. Mechanistically, we revealed that Fat1 promoted the nuclear‐cytoplasmic transportation of YAP1 (Yes‐associated protein 1), a critical executor of Hippo signaling, and a mutant form of YAP (YAP‐5SA), which can escape from LATS1/2‐mediated phosphorylation, rescued the Fat1‐mediated inhibition on the tumor‐initiating ability of NSCLC cells. This work prompts that Fat1 suppresses the tumor‐initiating ability of NSCLC cells by activating Hippo signaling. [ABSTRACT FROM AUTHOR]

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1–YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

A recent study in Scientific Reports identified glypican-3 (GPC3) as a novel extracellular interacting protein for FAT1 in hepato-cellular carcinoma (HCC) cells. FAT1 is a large transmembrane atypical cadherin with limited knowledge existing about its binding partners. While in Drosophila, dachsous (ds), another transmembrane member of the cadherin superfamily, is known to function as FAT1 ligand, no ligand is known in mammals so far. The revelation of GPC3 as a potential binding partner of FAT1 extracellular domain unfolds an opportunity to study potential triggers of FAT1 signaling in cancers. Available inhibitors of GPC3 in various phases of clinical trials also present an attractive option to curb GPC3-FAT1 signaling in tumors that overexpress these proteins.

Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology.

Prostate cancer (PCA) is an epithelial malignant tumor occurring in the prostate gland. It is the second most common male cancer in the world and one of the top five cancer deaths in men. To combat this disease, it is needed to identify important tumor suppressor genes and elucidate the molecular mechanisms. S100 calcium-binding protein A14 (S100A14), a member of the S100 family, is located on chromosome 1q21.3 and contains an EF-hand motif that binds calcium. S100A14 is involved in a variety of tumor biological processes in several types of cancers. Its expression level and related biological functions are tissue or tumor specific. However, its possible effects on prostate cancer are still unclear. Herein, we found the low expression of S100A14 in human prostate cancer tissues and cell lines. S100A14 suppressed the proliferation of prostate cancer cells and promoted cell apoptosis. Additionally, S100A14 suppressed the motility and EMT processes of prostate cancer cells. We further found S100A14 promoted the expression of FAT1 and activated the Hippo pathway, which, therefore, suppressed the prostate cancer progression. The in vivo assays confirmed that S100A14 suppressed tumor growth of prostate cancer cells through FAT1-mediated Hippo pathway in mice. In conclusion, we clarified the mechanism underlying S100A14 suppressing prostate cancer progression and, therefore, we thought S100A14 could serve as a tumor suppressor protein. [ABSTRACT FROM AUTHOR]

Immunotherapy is currently approved for CRC whose tumors have high MSI-H. To find additional biomarkers for immunotherapy in CRC, targeted sequencing was performed on tumor tissues from a discovery cohort of 161 CRC patients. Validation cohorts from the cBioPortal were also used for survival and tumor cell infiltration analyses. The FAT1 -mutated CRC group often co-occurred with MSI events and displayed a higher tumor mutational burden compared to the FAT1 wild-type CRC. Overall survival was higher in patients with FAT1 mutations than in patients with wild type FAT1. The altered PI3K-AKT pathway and immune pathways were enriched in the FAT1 -mutated CRC. A higher infiltration rate of immune cells including CD4+ T cells, CD8+ T cells, macrophages M1 and regulatory T cells were also observed in the colorectal tumors with FAT1 mutation compared to tumors with wild type FAT1. The results showed that CRC patients with FAT1 mutations exhibited an immunotherapy-favorable profile. • The altered PI3K-AKT pathway and immune pathways were enriched in the FAT1 -mutated CRC. • A higher infiltration rate of immune cells including CD4+ T cells, CD8+ T cells, macrophages M1 and regulatory T cells were observed in the colorectal tumors with FAT1 mutation compared to tumors with wild type FAT1. • CRC patients with FAT1 mutations exhibited the cooccurrence of MSI-H, high TMB, longer overall survival, and increased immune cell infiltration, and may benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Objective To clarify the mechanism of Fat1 on the proliferation of esophageal squamous cell carcinoma (ESCC). Methods KYSE450 cells were transfected with Plko.1-puro-GFP-shRNA-Fat1 plasmid and real time polymerase chain reaction (PCR) was used to verify the efficiency of Fat1 knockdown. The effects of Fat1 and extracellular regulated protein kinase (ERK) pathway inhibitor U0126 on the proliferation of ESCC cells were detected by methyl thiazolyl tetrazolium (MTT). Colony formation assay was used to detect the colony formation ability. Cell cycle was detected by live cell imaging. Western blot was used to observe the level of target protein. Mouse xenograft assay was applied to detect the effect of Fat1 knockdown on KYSE450 cell tumor growth. Immunohistochemistry was used to detect the expressions of related proteins in tumor sections. Results The efficiency of Fat1 knockdown was (77.1±6.9)% in Fat1 sh1 group and (77.7±7.1)% in Fat1sh2 group. Compared with the control group, the cell proliferation and the expression of p-ERK1/2 were significantly increased in Fat1 sh1 and Fat1sh2 group (P<0.05). After U0126 treatment, the effect of Fat1 knockdown on the proliferation of KYSE450 cells disappeared, and the expression of p-ERK1/2 in KYSE450 cells decreased to a level similar to that in the control group. The number of cell clones in the control group was (72±8), lower than (155±28) and (193±9) in the Fat1sh1 and Fat1sh2 groups, respectively (P<0.05). In KYSE450 cell, division time was shortened from 1 622±32 min in control group to 1 408±29 min in Fat1 sh1 group, the difference was statistically significant (P< 0.05). Compared with the control group, the tumor volume of Fat1 knockdown group increased significantly. The tumor weight of control group and Fat1 knockdown group were (0.224±0.028) g and (1.532±0.196) g, respectively, at 4 weeks after inoculation, and the difference was statistically significant ( P < 0. 05). Conclusion Fat1 inhibits cell proliferation via ERK signaling in ESCC. [ABSTRACT FROM AUTHOR]

Background: Endometrial cancer (EC) is the second most common female genital tract malignancy and has adverse outcome in the advanced stage. A prognostic marker is needed for marking an accurate prognostic. Objective: To evaluate expression and clinical outcome of CTNNB1 (β-catenin) and FAT atypical cadherin 1 (FAT1), by using immunohistochemical staining in EC type I. Materials and Methods: Seventy-two EC type I cases were selected from Songklanagarind Hospital with clinical data collection. All cases were evaluated by immunohistochemistry using antibodies against β-catenin and FAT1. Results: All cases of EC type I were β-catenin positive and FAT1 negative. Moderate and strong intensity (2+ and 3+) β-catenin cytoplasmic staining showed statistically significant association with low grade EC, and low risk of recurrence disease or metastasis (p<0.05). β-catenin nuclear staining was present in 19 of 28 cases (68%) of EC grade 1 and associated with low grade EC. β-catenin and FAT1 expression were not associated with 5-year overall survival in both univariate and multivariate analyses. Conclusion: β-catenin cytoplasmic staining may be associated with low grade EC, and helpful to predict recurrent risk. However, FAT1 and β-catenin expressions have no statically significant correlation with 5-year overall survival and cannot be used to determine the prognosis in type I EC patients. [ABSTRACT FROM AUTHOR]

FAT1, a substantial transmembrane protein, plays a pivotal role in cellular adhesion and cell signaling. Numerous studies have documented frequent alterations in FAT1 across various cancer types, with its aberrant expression being linked to unfavorable survival rates and tumor progression. In the present investigation, we employed bioinformatic analyses, as well as in vitro and in vivo experiments to elucidate the functional significance of FAT1 in pan-cancer, with a primary focus on lung cancer. Our findings unveiled FAT1 overexpression in diverse cancer types, including lung cancer, concomitant with its association with an unfavorable prognosis. Furthermore, FAT1 is intricately involved in immune-related pathways and demonstrates a strong correlation with the expression of immune checkpoint genes. The suppression of FAT1 in lung cancer cells results in reduced cell proliferation, migration, and invasion. These collective findings suggest that FAT1 has potential utility both as a biomarker and as a therapeutic target for lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ding, Huang, Wu, Chen, Hua, Liu, Li, Liu and Chen.)

Background: Previous studies found that FAT1 was recurrently mutated and aberrantly expressed in multiple cancers, and the loss function of FAT1 promoted the formation of cancer-initiating cells in several cancers. However, in some types of cancer, FAT1 upregulation could lead to epithelial-mesenchymal transition (EMT). The role of FAT1 in cancer progression, which appears to be cancer-type-specific, is largely unknown., Methods: QRT-PCR and immunochemistry were used to verify the expression of FAT1 in non-small cell lung cancer (NSCLC). QRT-PCR and Western blot were used to detect the influence of siFAT1 knockdown on the expression of potential targets of FAT1 in NSCLC cell lines. GEPIA, KM-plotter, CAMOIP, and ROC-Plotter were used to evaluate the association between FAT1 and clinical outcomes based on expression and clinical data from TCGA and immune checkpoint inhibitors (ICI) treated cohorts., Results: We found that FAT1 upregulation was associated with the activation of TGF-β and EMT signaling pathways in NSCLC. Patients with a high FAT1 expression level tend to have a poor prognosis and hard to benefit from ICI therapy. Genes involved in TGF-β/EMT signaling pathways ( SERPINE1, TGFB1/2, and POSTN ) were downregulated upon knockdown of FAT1 . Genomic and immunologic analysis showed that high cancer-associated fibroblast (CAF) abundance, decreased CD8 + T cells infiltration, and low TMB/TNB were correlated with the upregulation of FAT1 , thus promoting an immunosuppressive tumor microenvironment (TME) which influence the effect of ICI-therapy., Conclusion: Our findings revealed the pattern of FAT1 upregulation in the TME of patients with NSCLC, and demonstrated its utility as a biomarker for unfavorable clinical outcomes, thereby providing a potential therapeutic target for NSCLC treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)