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The Pattern Of Invasion (POI) of tumor cells into adjacent normal tissues clinically predicts postoperative tumor metastasis/recurrence of early oral squamous cell carcinoma (OSCC), but the mechanisms underlying the development of these subtypes remain unclear. Focusing on the highest score of POIs (Worst POI, WPOI) present within each tumor, we observe a disease progression-driven shift of WPOI towards the high-risk type 4/5, associated with a mesenchymal phenotype in advanced OSCC. WPOI 4-5-derived cancer-associated fibroblasts (CAFsWPOI4-5), characterized by high oxytocin receptor expression (OXTRHigh), contribute to local-regional metastasis. OXTRHigh CAFs induce a desmoplastic stroma and CCL26 is required for the invasive phenotype of CCR3+ tumors. Mechanistically, OXTR activates nuclear ERK5 transcription signaling via Gαq and CDC37 to maintain high levels of OXTR and CCL26. ERK5 ablation reprograms the pro-invasive phenotype of OXTRHigh CAFs. Therefore, targeting ERK5 signaling in OXTRHigh CAFs is a potential therapeutic strategy for OSCC patients with WPOI 4-5. Worst pattern of invasion (WPOI) is a parameter used to quantify tumor invasiveness of oral squamous cell carcinoma (OSCC). Here the authors show that a fibroblast subset characterized by the expression of the oxytocin receptor is enriched in highly invasive WPOI 4-5 OSCC tumors and can be targeted to reduce the desmoplastic stroma and tumor metastasis. [ABSTRACT FROM AUTHOR]

Innate immune signalling mediated by the nucleotide-binding and oligomerization domain (NOD) receptors for pathogen-associated constituents regulates the response to intracellular peptidoglycans present in Gram-negative and Gram-positive bacteria. Recently, Yeretssian et [...]

Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKy or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene ([Sharpin.sup.cpdm/cpdm]) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling., Members of the TNF receptor superfamily (TNFRSF) exert pleiotropic effects in immune and non-immune tissues (1) and their signalling is regulated by different types of ubiquitin chains (2-4). We and [...]

The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4-2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from [Ndfip1.sup.-/-] with [Ndfip1.sup.+/+] mice exposed to Fe reveals that [Ndfip1.sup.-/-] brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons. cobalt | iron | Nedd4-2 | ubiquitin

FAS (also called APO-1 and CD95) and its physiological ligand, FASL, regulate apoptosis of unwanted or dangerous cells, functioning as a guardian against autoimmunity and cancer development (1-4). Distinct cell [...]

A flexible mouse model of liver cancer is used to search for spontaneous mutations arising in tumors initiated by different oncogenic lesions and it is then compared to alterations observed in human cancers. The model has not only identified two oncogenes in the same focal amplification that cooperate during tumerogenesis but has also highlighted the use of integrating mouse models and cancer genomics for the functional annotation of cancer genes.