Dataset Information

Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.

ABSTRACT: PURPOSE:Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption, and high-risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. NOTCH1 is among the most frequently mutated genes in both HPV-positive and HPV-negative HNSCC. These mutations are predicted to inactivate the function of Notch. Other studies have argued the opposite-Notch signaling is increased in HNSCC. EXPERIMENTAL DESIGN:To assess the role of Notch signaling in HPV-positive and HPV-negative HNSCC, we utilized genetically engineered mouse (GEM) models for conventional keratinizing HNSCC, in which either HPV16 E6 and E7 oncoproteins or a gain-of-function mutant p53 are expressed, and in which we inactivated canonical Notch signaling via expression of a dominant negative form of MAML1 (DNMAML1), a required transcriptional coactivator of Notch signaling. RESULTS:Loss of canonical Notch signaling increased tumorigenesis in both contexts and also caused an increase in nuclear ?-catenin, a marker for increased tumorigenic potential. When combined with loss of canonical Notch signaling, HPV oncogenes led to the highest frequency of cancers overall and the largest number of poorly differentiated (high-grade) cancers. CONCLUSIONS:These findings inform on the contribution of loss of canonical Notch signaling in head and neck carcinogenesis.

SUBMITTER: Nyman PE

PROVIDER: S-EPMC6295262 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.

Nyman Patrick E PE Buehler Darya D Lambert Paul F PF

Clinical cancer research : an official journal of the American Association for Cancer Research 20180807 24

<h4>Purpose</h4>Head and neck squamous cell carcinoma (HNSCC), a common cancer worldwide, is etiologically associated with tobacco use, high alcohol consumption, and high-risk human papillomaviruses (HPV). The Notch signaling pathway, which is involved in cell differentiation decisions with differential downstream targets and effects depending on tissue type and developmental stage, has been implicated in human HNSCC. <i>NOTCH1</i> is among the most frequently mutated genes in both HPV-positive ...[more]

PMID: 30087145

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Project description:We analyzed transcriptional data from 104 HPV+ (Human papillomavirus) HNSCC (head and neck squamous cell carcinoma) tumors together with two publicly available sources to identify highly robust transcriptional programs (modules) which could be detected consistently despite heterogeneous sequencing and quantification methodologies. Among 22 modules identified, we found a single module that naturally subclassifies HPV+ HNSCC tumors based on a bimodal pattern of gene expression, clusters all atypical features of HPV+ HNSCC biology into a single subclass, and predicts patient outcome in four independent cohorts. The subclass-defining gene set was strongly correlated with Nuclear factor kappa B (NF-κB) target expression. Tumors with high expression of this NF-κB module were rarely associated with activating PIK3CA alterations or viral integration, and also expressed higher levels of HPHPV E2 and had decreased APOBEC mutagenesis. Alternatively, they harbored inactivating alterations of key regulators of NF-κB, TNF receptor associated factor 3 (TRAF3), and cylindromatosis (CYLD), as well as retinoblastoma protein (RB1). HPV+ HNSCC cells in culture with experimental depletion of TRAF3 or CYLD displayed increased expression of the subclass-defining genes, as well as robust radio-sensitization, thus recapitulating both the tumor transcriptional state and improved treatment response observed in patient data. Across all gene sets investigated, methylation to expression correlations were the strongest for the subclass-defining, NF-κB-related genes. Increased tumor-infiltrating CD4+ T cells and increased Estrogen receptors alpha (ERα) expression were identified in NF-κB active tumors. Based on the relatively high rates of cure in HPV+ HNSCC, deintensification of therapy to reduce treatment-related morbidity is being studied at many institutions. Tumor subclassification based on oncogenic subtypes may help guide the selection of therapeutic intensity or modality for patients with HPV+ HNSCC.

Project description:BACKGROUND:Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, acts as tumor suppressor in prostate cancer but the role of ABI1 in EMT is not clear. METHODS:To investigate the molecular mechanism by which loss of ABI1 contributes to tumor progression, we disrupted the ABI1 gene in the benign prostate epithelial RWPE-1 cell line and determined its phenotype. Levels of ABI1 expression in prostate organoid tumor cell lines was evaluated by Western blotting and RNA sequencing. ABI1 expression and its association with prostate tumor grade was evaluated in a TMA cohort of 505 patients and metastatic cell lines. RESULTS:Low ABI1 expression is associated with biochemical recurrence, metastasis and death (p =?0.038). Moreover, ABI1 expression was significantly decreased in Gleason pattern 5 vs. pattern 4 (p =?0.0025) and 3 (p =?0.0012), indicating an association between low ABI1 expression and highly invasive prostate tumors. Disruption of ABI1 gene in RWPE-1 cell line resulted in gain of an invasive phenotype, which was characterized by a loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 spheroids. Through RNA sequencing and protein expression analysis, we discovered that ABI1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of ABI1. Furthermore, an increase in STAT3 phosphorylation upon ABI1 inactivation and the evidence of a high-affinity interaction between the FYN SH2 domain and ABI1 pY421 support a model in which ABI1 acts as a gatekeeper of non-canonical WNT-EMT pathway activation downstream of the FZD2 receptor. CONCLUSIONS:ABI1 controls prostate tumor progression and epithelial plasticity through regulation of EMT-WNT pathway. Here we discovered that ABI1 inhibits EMT through suppressing FYN-STAT3 activation downstream from non-canonical WNT signaling thus providing a novel mechanism of prostate tumor suppression.

Dataset Information

Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.

Publications

Loss of Function of Canonical Notch Signaling Drives Head and Neck Carcinogenesis.

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