Similar Datasets
Project description:MUC1-C DICTATES NEUROENDOCRINE LINEAGE SPECIFICATION IN PANCREATIC DUCTAL ADENOCARCINOMAS
| PRJNA754087 | ENA
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
2019-12-02 | GSE139335 | GEO
Project description:MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer
| PRJNA579338 | ENA
Project description:Patients with rare pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression associates with (i) advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.
2024-05-21 | GSE267722 | GEO
Project description:The aberrant overexpression of mucin 1 (MUC1) and human epidermal growth factor receptor 2 (HER2) are often observed in breast cancer. However, the role of concomitant of MUC1/HERR2 in the development of breast cancer has not been fully illustrated. Following analysis public microarray datasets that revealed a correlation of double positive of MUC1 and HER2 to a worse clinical outcome, we generated a mouse model overexpressing both Her2 and MUC1 cytoplasmic domain (MUC1-CD) to investigate their interaction in mammary carcinogenesis. Coexpression of Her2 and MUC1-CD confers growth advantage and promotes the development of spontaneous mammary tumors. Genomic analysis uncovers that enforced expression of MUC1-CD and Her2 induces mammary tumor lineage plasticity which is supported by gene reprogramming and mammary stem cell enrichment. With gain- and loss-of function strategies, we show that coexpression of Her2 and MUC1-CD was associated with down-regulation of TCA cycle genes in tumors. Importantly, the reduction of TCA cycle genes induced by MUC1-CD is is significantly connected to the poor prognosis in HER2+ breast cancer patients. In addition, MUC1 augments Her2 signaling pathway by inducing Her2/Egfr dimerization. These findings collectively demonstrate the vital role of MUC1-CD/Her2 collaboration in shaping mammary tumor landscape and highlight the prognostic and therapeutic implication of MUC1 in patients with Her2+ breast cancer.
2022-03-10 | GSE198239 | GEO
Project description:Small cell lung cancer (SCLC) is a recalcitrant malignancy associated with dysregulation of MYC signaling and the CDK-RB-E2F axis. We report that expression of the oncogenic MUC1-C protein in SCLC cells integrates activation of MYC and the E2F pathway. MUC1-C drives MYC and E2F target genes and regulates the G2/M checkpoint, mitotic spindle pathway and replication stress response (RSR). We further show that MUC1-C MYC signaling (i) induces NOTCH2, a marker of pulmonary neuroendocrine (NE) stem cells that are the proposed cell of SCLC origin, (ii) drives NE differentiation, as evidenced by expression of ASCL1 and POU3F2/BRN2, and (iii) promotes self-renewal capacity and tumorigenicity of SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 significantly associates with the MYC pathway. These findings uncover a master role for MUC1-C in promoting progression of the SCLC stem cell state and support MUC1-C as a potential target for SCLC treatment.
2023-01-12 | GSE159801 | GEO
Project description:Mucin 1 (MUC1) is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1 in the pathogenesis of squamous cell carcinomas (SCCs). The present work demonstrates that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCCs) and, as determined by scRNA-seq analysis, is expressed in the malignant cell populations of HNSCC tumors. Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and interferon (IFN) regulatory factors, and (iii) downstream IFN-stimulated genes (ISGs). MUC1-C integrates STAT1 with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. We also show that MUC1-C/STAT1 signaling activates the NFE2L2 gene and, in turn, MUC1-C binds directly to NRF2 in regulating redox balance. In extending these HNSCC cell dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity and tumorigenicity. These results indicate that MUC1-C is a common effector that integrates STAT1-mediated chronic inflammation with regulation of the ∆Np63, SOX2, NRF2 and NOTCH3 TFs. Our findings indicate that MUC1-C drives progression of the HNSCC CSC state and is a target for advanced HNSCC treatment.
2024-04-23 | GSE252287 | GEO
Project description:Small cell lung cancer (SCLC) is a recalcitrant malignancy associated with dysregulation of MYC signaling and the CDK-RB-E2F axis. We report that expression of the oncogenic MUC1-C protein in SCLC cells integrates activation of MYC and the E2F pathway. MUC1-C drives MYC and E2F target genes and regulates the G2/M checkpoint, mitotic spindle pathway and replication stress response (RSR). We further show that MUC1-C MYC signaling (i) induces NOTCH2, a marker of pulmonary neuroendocrine (NE) stem cells that are the proposed cell of SCLC origin, (ii) drives NE differentiation, as evidenced by expression of ASCL1 and POU3F2/BRN2, and (iii) promotes self-renewal capacity and tumorigenicity of SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 significantly associates with the MYC pathway. These findings uncover a master role for MUC1-C in promoting progression of the SCLC stem cell state and support MUC1-C as a potential target for SCLC treatment.
2023-01-12 | GSE192475 | GEO
Project description:Mucin 1 (MUC1) is a transmembrane mucin expressed at the apical surface of epithelial cells at different mucosal surfaces including breast and intestine. The MUC1 extracellular domain contains a variable number of tandem repeats (VNTR) of 20 amino acids, which are heavily O-linked glycosylated. Monoclonal antibodies against the MUC1 VNTR can be powerful tools because of their multiplicity of binding and possible applications in the diagnosis and treatment of MUC1-expressing cancers. One such antibody is the hybridoma mouse monoclonal 139H2 which is also widely used as a research tool to study non-cancer MUC1. Here we report direct mass spectrometry-based sequencing of hybridoma-derived 139H2 IgG, which enabled reverse engineering of a recombinant 139H2.
2024-03-18 | PXD043489 | Pride
Project description:Goal of study: To determine differentially expressed genes with potential roles in tolerance and immunity in MUC1-immunized WT and MUC1.Tg mice WT (C57Bl/6) and MUC1.Tg mice were immunized (i.v.) with dendritic cells loaded with sythetic, human MUC1 peptide. At 24h and 72h splenic RNA from vaccination groups (n=3) was pooled and microarray performed.
2013-01-16 | E-GEOD-43503 | biostudies-arrayexpress