Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy
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PROVIDER: PRJNA1158796 | ENA |
REPOSITORIES: ENA
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Project description:Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) represent a spectrum of malignancies that invariably become resistant to treatment with targeted and cytotoxic agents. There is no known common pathway responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC and NEPC in association with poor clinical outcomes. The present results demonstrate that the oncogenic MUC1-C protein is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). We show that MUC1-C-mediated ENZ and DTX resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species (ROS) necessary for self-renewal capacity. Common dependence of these drug-resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state thus identified a potential new target for their treatment. cIn this context, we further demonstrate that targeting MUC1-C with an antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC and NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings reveal a shared MUC1-C-dependent pathway in drug-resistant CRPC and NEPC progression and identify MUC1-C as a target for their treatment with an ADC.
2025-01-02 | GSE276750 | GEO
Project description:Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) represent a spectrum of malignancies that invariably become resistant to treatment with targeted and cytotoxic agents. There is no known common pathway responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC and NEPC in association with poor clinical outcomes. The present results demonstrate that the oncogenic MUC1-C protein is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). We show that MUC1-C-mediated ENZ and DTX resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species (ROS) necessary for self-renewal capacity. Common dependence of these drug-resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state thus identified a potential new target for their treatment. cIn this context, we further demonstrate that targeting MUC1-C with an antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC and NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings reveal a shared MUC1-C-dependent pathway in drug-resistant CRPC and NEPC progression and identify MUC1-C as a target for their treatment with an ADC.
2025-01-02 | GSE276890 | GEO
Project description:Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy
| PRJNA1159347 | ENA
Project description:A microbial-inspired antibody-drug conjugate for cancer immunotherapy
| PRJNA1077275 | 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: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:In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical cancer in China have increased significantly. Screening and identification of reliable biomarkers and candidate drug targets of cervical cancer are urgent to improve the survival rate and quality of life of patients. In this study, we demonstrated that MUC1 displayed elevation in cervical squamous cell carcinoma (CSCC). The expression of MUC1 was higher in neoplastic compared with non-neoplastic tissues of the cervix, indicated its potential in early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in CSCC. MUC1 overexpression promoted the proliferation and metastasis abilities of cervical cancer cells. MUC1 could regulate ERK phosphorylation, then upregulated ITGA2 and ITGA3 expression. Further knockdown of ITGA2 and ITGA3 significantly inhibited tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen with MUC1-siRNA and ERK inhibitor in vivo, founding that the combination of drugs achieved better results in animals with xenograft compared with targeting MUC1 alone. Taken together, we discovered a novel regulatory MUC1/ERK/ITGA2/3 pathway in cervical cancer that may serve as potential biomarkers and therapeutic targets in the future.
2023-08-21 | GSE241017 | GEO
Project description:Generating antitumor immune responses requires the phagocytosis of tumor cells and subsequent cross-presentation of tumor-derived antigens by antigen-presenting cells. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-drug conjugate (ADC) that targets the “don’t eat me” signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes the phagocytosis of cancer cells followed by the release and activation of LLO to form pores on phagolysosomal membranes that allow cytosolic entry of tumor-derived contents, leading to enhanced antigen cross-presentation of tumor-derived peptides and activation of cytosolic immune sensors. CD47-LLO treatment in vivo significantly inhibited the growth of both localized and metastatic tumors and improved animal survival as monotherapy or in combination with checkpoint blockade. Together, these results demonstrate that designing ADCs to promote immune recognition of tumor cells represents a promising therapeutic strategy for treating multiple cancers.
2024-12-01 | GSE255937 | GEO