Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it's downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.
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http://dx.doi.org/10.7554/eLife.46551 | DOI Listing |
Front Oncol
October 2024
School of Physics, Changchun University of Science and Technology, Changchun, China.
Purposes: Osimertinib, one of the third-generation -tyrosine kinase inhibitors (TKIs) designed to target T790M mutation, significantly improves the prognosis of lung cancer. However, drug resistance still happens and amplification is responsible for one of the main causes. Fluorescence hybridization (FISH) is the gold standard for amplification detection, but fundamentally limited by observer subjectivity.
View Article and Find Full Text PDFThis study aimed to examine the influence of the Neuregulin-1 (NRG1)/ERBB4 signaling pathway on the function of human pulmonary artery endothelial cells (HPAECs) and investigate the underlying mechanisms. Enzyme-linked immunosorbent assay indicated that ERBB4 levels in the serum of patients with pulmonary embolism (PE) were significantly higher than those of healthy controls ( < 0.05).
View Article and Find Full Text PDFSchizophrenia (Heidelb)
September 2024
Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.
How early in life stress-immune related environmental factors increase risk predisposition to schizophrenia remains unknown. We examined if pro-inflammatory changes perturb the brain epidermal growth factor (EGF) system, a system critical for neurodevelopment and mature CNS functions including synaptic plasticity. We quantified genes from key EGF and immune system pathways for mRNA levels and eight immune proteins in post-mortem dorsolateral prefrontal (DLPFC; Brodmann's Area (BA) 46) and orbitofrontal (OFC; BA11) cortices from people with schizophrenia, mood disorders and neurotypical controls.
View Article and Find Full Text PDFJ Neurosci
October 2024
Genetics of Neuronal Signaling Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al.
View Article and Find Full Text PDFJ Fungi (Basel)
July 2024
Department of Periodontics & Endodontics, School of Dental Medicine, University at Buffalo, Buffalo, NY 14214, USA.
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