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MUC1-C DICTATES NEUROENDOCRINE LINEAGE SPECIFICATION IN PANCREATIC DUCTAL ADENOCARCINOMAS

ABSTRACT: MUC1-C DICTATES NEUROENDOCRINE LINEAGE SPECIFICATION IN PANCREATIC DUCTAL ADENOCARCINOMAS

PROVIDER: PRJNA754087 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15425126_1.fastq.gz	Fastqsanger.gz
	SRR15425126_2.fastq.gz	Fastqsanger.gz
	SRR15425127_1.fastq.gz	Fastqsanger.gz
	SRR15425127_2.fastq.gz	Fastqsanger.gz
	SRR15425128_1.fastq.gz	Fastqsanger.gz

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MUC1-C DICTATES NEUROENDOCRINE LINEAGE SPECIFICATION IN PANCREATIC DUCTAL ADENOCARCINOMAS

Project description:MUC1-C drives neuroendocrine lineage plasticity in pancreatic adenocarcinomas

2021-08-13 | GSE181961 | GEO

MUC1-C dictates neuroendocrine lineage specification in pancreatic ductal adenocarcinomas.

Project description:Pancreatic ductal adenocarcinomas (PDAC) and poorly differentiated pancreatic neuroendocrine (NE) carcinomas are KRAS mutant malignancies with a potential common cell of origin. PDAC ductal, but not NE, lineage traits have been associated with cell-intrinsic activation of interferon (IFN) pathways. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1-C), which evolved to protect mammalian epithelia from loss of homeostasis, is aberrantly overexpressed in KRAS mutant PDAC tumors and cell lines. We show that MUC1-C is necessary for activation of the type I and II IFN pathways and for expression of the Yamanaka OCT4, SOX2, KLF4 and MYC (OSKM) pluripotency factors. Our results demonstrate that MUC1-C integrates IFN signaling and pluripotency with NE dedifferentiation by forming a complex with MYC and driving the (i) achaete-scute homolog 1 and BRN2/POU3F2 neural, and (ii) NOTCH1/2 stemness transcription factors. Of translational relevance, targeting MUC1-C genetically and pharmacologically in PDAC cells (i) suppresses OSKM, NE dedifferentiation and NOTCH1/2, and (ii) inhibits self-renewal capacity and tumorigenicity. In PDAC tumors, we show that MUC1 significantly associates with activation of IFN signaling, MYC and NOTCH, and that upregulation of the MUC1-C → MYC pathway confers a poor prognosis. These findings indicate that MUC1-C dictates PDAC NE lineage specification and is a potential target for the treatment of recalcitrant pancreatic carcinomas with NE dedifferentiation.

| S-EPMC8832436 | biostudies-literature

PANCREATIC DUCTAL ADENOCARCINOMAS RESISTANT TO KRAS INHIBITION ARE DRUGGABLE WITH AN ANTI-MUC1-C ADC

Project description:Treatment of pancreatic ductal carcinomas (PDACs) has been advanced by the development of KRAS mutant inhibitors. Despite this progress, PDACs invariably develop resistance to these agents by mechanisms that largely remain unclear. The MUC1 gene, which encodes an oncogenic MUC1-C protein, is upregulated in PDAC KRAS G12D tumors. We report that treatment of PDAC cells with the selective KRAS G12D MRTX1133 inhibitor is associated with induction of MUC1-C expression. We show that KRAS G12D inhibition activates a MUC1-C/NF-B p65 auto-inductive pathway. Our results further demonstrate that MUC1-C drives resistance to MRTX1133 by activating the inflammatory IFN type I and II pathways. Of clinical relevance, targeting MUC1-C genetically and pharmacologically reverses MRTX1133 resistance and is synergistic in combination with MRTX1133 treatment. In leveraging MRTX1133-induced upregulation of MUC1-C expression, an anti-MUC1-C (M1C) antibody-drug conjugate (ADC) is highly effective against MRTX1133-resistant PDAC KRAS G12D cell lines, patient-derived organoids and PDX tumor xenograft models. These findings demonstrate that MUC1-C confers resistance of PDAC KRAS G12D mutant cells to MRTX1133 and identify MUC1-C as a target for M1C ADC treatment of PDAC patients who are refractory to MRTX1133 treatment.

2025-04-08 | GSE293756 | GEO

PANCREATIC DUCTAL ADENOCARCINOMAS RESISTANT TO KRAS INHIBITION ARE DRUGGABLE WITH AN ANTI-MUC1-C ADC

Project description:PANCREATIC DUCTAL ADENOCARCINOMAS RESISTANT TO KRAS INHIBITION ARE DRUGGABLE WITH AN ANTI-MUC1-C ADC

| PRJNA1246165 | ENA

MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

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

MUC1-C DEPENDENCE FOR PROGRESSION OF PANCREATIC NEUROENDOCRINE TUMORS IDENTIFIES A DRUGGABLE TARGET FOR TREATMENT OF THIS RARE CANCER

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

Expression data from human pancreatic ductal adenocarcinomas by stroma types

Project description:Expression data from human pancreatic ductal adenocarcinomas by stroma types

| PRJNA661040 | ENA

MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

Project description:MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

| PRJNA579338 | ENA

MUC1-C IS A MASTER REGULATOR OF SMALL CELL LUNG CANCER PROGRESSION

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

MUC1-C PROMOTES CHRONIC INFLAMMATION IN THE PROGRESSION OF HEAD AND NECK SQUAMOUS CELL CARCINOMAS

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

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