A5078157913- Lung Cancer Research Studies
- Glycosylation and Glycoproteins Research
- Cancer Genomics and Diagnostics
- Cholangiocarcinoma and Gallbladder Cancer Studies
- RNA modifications and cancer
- Infectious Diseases and Mycology
- Lung Cancer Treatments and Mutations
- Head and Neck Cancer Studies
- PI3K/AKT/mTOR signaling in cancer
- Molecular Biology Techniques and Applications
- Cancer-related gene regulation
- Chronic Lymphocytic Leukemia Research
- Cancer-related molecular mechanisms research
- interferon and immune responses
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- Neuroendocrine Tumor Research Advances
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Polyomavirus and related diseases
- Protein Tyrosine Phosphatases
- Plant Virus Research Studies
- RNA and protein synthesis mechanisms
- Ferroptosis and cancer prognosis
- Lung Cancer Diagnosis and Treatment
Dana-Farber Cancer Institute
2022-2024
Harvard University
2022-2024
Abstract The long non-coding RNA X-inactive specific transcript (lncRNA XIST) and MUC1 gene are dysregulated in chronic inflammation cancer; however, there is no known interaction of their functions. present studies demonstrate that MUC1-C regulates XIST lncRNA levels by suppressing the RBM15/B, WTAP METTL3/14 components m6A methylation complex associate with A repeats. also suppresses YTHDF2-CNOT1 deadenylase recognizes sites contributes to decay increases stability expression. In support...
The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, promotes oncogenesis association with chronic inflammation. Aberrant expression cancers has been linked depletion and dysfunction T cells the tumor microenvironment. In contrast, there is no known involvement regulation natural killer (NK) cell function.Targeting genetically pharmacologically cancer was performed assess effects on intracellular surface MHC class I chain-related polypeptide A...
IntroductionOsimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring exon 19 deletions or L858R mutations. Patients treated osimertinib invariably develop acquired resistance by mechanisms involving additional mutations, MET amplification, and other pathways. There no known involvement oncogenic MUC1-C protein in resistance.MethodsH1975/EGFR (L858R/T790M) patient-derived cells were investigated dependence...
Abstract The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to for self-renewal in progression human cancers has emphasized need development anti-MUC1-C agents. However, there are presently no approved small molecules targeting MUC1-C-dependent CSCs. In screening molecules, we identified salinomycin (SAL), an inducer ferroptosis, as potent inhibitor signaling. We demonstrate that SAL suppresses expression by disrupting...
Abstract The MUC1 gene evolved in mammals for adaptation of barrier tissues response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA loss homeostasis. There is no known intersection with or paraspeckles. Here, we demonstrate that MUC1-C subunit plays an essential role regulating expression. activates induction NEAT1_1 NEAT1_2 isoforms by NF-κB- MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression SFPQ, NONO FUS RNA binding proteins (RBPs)...
Abstract The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 IRF1 are essential effectors type I II IFN pathways. Here, we report MUC1-C is necessary for PBRM1 expression it forms a nuclear with triple-negative breast (TNBC) cells. Analysis global transcriptional (RNA-seq) accessibility (ATAC-seq) profiles further demonstrated...
Abstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated the inflammatory NF-κB pathway cells. There no known involvement of regulation COMPASS family H3K4 methyltransferases. We find regulates (i) bulk methylation levels, and (ii) SET1A/SETD1A WDR5 genes an NF-κB-mediated mechanism. importance regulating SET1A complex supported demonstration drive expression FOS, ATF3 other AP-1 members....
Abstract Merkel cell carcinoma (MCC) is an aggressive malignancy with neuroendocrine (NE) features, limited treatment options, and a lack of druggable targets. There no reported involvement the MUC1-C oncogenic protein in MCC progression. We show here that broadly expressed MCCs at higher levels polyomavirus (MCPyV)-positive (MCCP) relative to MCPyV-negative (MCCN) tumors. Our results further demonstrate MCCP, as well MCCN, lines regulates common sets signaling pathways related RNA...
Abstract Small cell lung cancer (SCLC) is a recalcitrant malignancy defined by subtypes on the basis of differential expression ASCL1, NEUROD1, and POU2F3 transcription factors. The MUC1-C protein activated in pulmonary epithelial cells exposure to environmental carcinogens promotes oncogenesis; however, there no known association between SCLC. We report that expressed classic neuroendocrine (NE) SCLC-A, variant NE SCLC-N non-NE SCLC-P activates MYC pathway these subtypes. In SCLC...
Activation of the MUC1-C protein promotes lineage plasticity, epigenetic reprogramming, and cancer stem cell (CSC) state. The present studies performed on enriched populations triple-negative breast (TNBC) CSCs demonstrate that is essential for integrating activation glycolytic pathway genes with self-renewal tumorigenicity. further integrates suppression mitochondrial DNA (mtDNA) encoding components Complexes I-V. repression mtDNA explained by MUC1-C-mediated (i) downregulation...
Abstract The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less known about involvement the pathogenesis squamous cell carcinomas (SCCs). Here, we report that MUC1 gene upregulated advanced head neck SCCs (HNSCCs). Studies HNSCC lines demonstrate subunit regulates expression (i) RIG-I MDA5 pattern recognition receptors, (ii) STAT1 interferon (IFN) regulatory factors, (iii) downstream IFN-stimulated genes (ISGs)....
Abstract Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring exon 19 deletions or L858R mutations. Patients treated osimertinib invariably develop acquired resistance by mechanisms involving additional mutations, MET amplification and other pathways. There no known involvement oncogenic MUC1-C protein in resistance. Methods: H1975/EGFR(L858R/T790M) patient-derived cells (EMT, amplified,...
<p>Expression of MUC1 in HNSCC tumors and effects silencing MUC1-C on cell clonogenicity. <b>A,</b> Analysis primary (P) metastatic (M) tissues for expression using the GSE136037 dataset. <b>B,</b> CAL27/CshRNA MUC1shRNA cells were analyzed mRNA levels (left). The results (mean ± SD four determinations) are expressed as relative compared with that obtained CshRNA (assigned a value 1; left). Lysates immunoblotted antibodies against indicated proteins (right)....
<p>MUC1-C regulates a global transcriptional program enriched for STAT/IRF signaling in HNSCC cells. <b>A,</b> RNA-seq was performed on CAL27/tet-MUC1shRNA and HSC3/tet-MUC1shRNA cells treated with vehicle or DOX 7 days. Volcano plots depicting downregulated (blue) upregulated (red) DEGs (FDR<0.05; FC>2). Highlighted are the top by significance magnitude. <b>B,</b> Common genes CAL27 HSC3 MUC1-C silencing. <b>C,</b> Purified chromatin from days...
<p>MUC1-C regulates NOTCH3 expression and HNSCC cell self-renewal capacity. <b>A,</b> CAL27/tet-MUC1shRNA cells treated with vehicle or DOX for 7 days were analyzed mRNA levels. The results (mean ± SD of four determinations) are expressed as relative levels compared that obtained vehicle-treated (assigned a value 1; left). Lysates immunoblotted antibodies against the indicated proteins (right). <b>B,</b> GSEA RNA-seq data from using REACTOME SIGNALING BY gene...
<p>Regulation of ∆Np63 expression in HSC3 cells.</p>
<p>MUC1-C/STAT1 signaling regulates ∆Np63 expression. <b>A,</b> CAL27/tet-MUC1shRNA cells treated with vehicle or DOX for 7 days were analyzed <i>∆Np63</i> gene transcription (left) and mRNA (right) levels. The results (mean ± SD of four determinations) are expressed as relative levels compared that obtained vehicle-treated (assigned a value 1). <b>B,</b> CAL27/CshRNA CAL27/STAT1shRNA <b>C,</b> Schema the highlighting localization PLS...
<p>Effects of targeting MUC1-C on effectors the type I and II IFN pathways.</p>
<p>Single-cell profiling of the expression MUC1 and related genes in HNSCC. <b>A–C,</b> UMAP representation total cells analyzed from GSE118389 dataset HPV-negative/HPV-positive HNSCC samples (<b>A</b>), HPV-negative (<b>B</b>), HPV-positive (<b>C</b>) (left). Distributions individual (middle). each cell type (right). <b>D,</b> Model depicting current findings that MUC1-C integrates activation STAT1, IFN I/II signaling ISG...
<p>MUC1-C regulates expression of PRRs and effectors the type I II IFN pathways. <b>A,</b> CAL27/tet-MUC1shRNA cells treated with vehicle or DOX for 6 days were analyzed RIG-I MDA5 mRNA levels. The results (mean ± SD four determinations) are expressed as relative levels compared that obtained vehicle-treated (assigned a value 1). <b>B,</b> CAL27 expressing indicated vectors 7 days. Lysates immunoblotted antibodies against proteins. <b>C,</b> STAT1,...
<p>Single-cell profiling of the expression MUC1 and related genes in HNSCC.</p>
<p>Regulation of SOX2 expression in HSC3 cells.</p>
<p>MUC1-C/STAT1 signaling regulates ∆Np63 expression. <b>A,</b> CAL27/tet-MUC1shRNA cells treated with vehicle or DOX for 7 days were analyzed <i>∆Np63</i> gene transcription (left) and mRNA (right) levels. The results (mean ± SD of four determinations) are expressed as relative levels compared that obtained vehicle-treated (assigned a value 1). <b>B,</b> CAL27/CshRNA CAL27/STAT1shRNA <b>C,</b> Schema the highlighting localization PLS...
<p>MUC1-C regulates NOTCH3 expression and HNSCC cell self-renewal capacity. <b>A,</b> CAL27/tet-MUC1shRNA cells treated with vehicle or DOX for 7 days were analyzed mRNA levels. The results (mean ± SD of four determinations) are expressed as relative levels compared that obtained vehicle-treated (assigned a value 1; left). Lysates immunoblotted antibodies against the indicated proteins (right). <b>B,</b> GSEA RNA-seq data from using REACTOME SIGNALING BY gene...