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Presence of inflammatory factors in the tumor microenvironment is well-documented yet their specific role in tumorigenesis is elusive. The core inflammatory pathways like the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway are conserved in Drosophila . We induced GFP-marked epithelial tumors by expressing activated oncogenic forms of Ras V12 or Yorkie ( Yki 3SA , mammalian YAP) in scribble deficient cells ( scrib RNAi , mammalian SCRIB) to study the role of inflammatory factors in tumorigenesis. Similar to Ras V12 scrib RNAi , we found that Yki 3SA scrib RNAi form invasive neoplastic lethal tumors that induce a systemic inflammatory response. We identified Cactus (Cact, mammalian IκBα), the negative regulator of TLR, as a key player in tumor growth. Cact accumulates in the cytoplasm in Drosophila tumor models, similar to squamous cell carcinoma in mice models and human patients where cytoplasmic IκBα favors oncogenic transformation. Further, cact is transcriptionally upregulated in tumors, and downregulation of Cact affects tumor growth. We investigated if TLR or TNF pathway affect tumor growth through activation of Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). Genetically manipulating levels of TLR components or TNF receptors showed that Cact acts upstream of JNK signaling and regulates JNK via a non-canonical mechanism during tumorigenesis. Further, Hippo coactivator Yki transcriptionally regulates cact expression, and downregulation of Yki or Cact is sufficient to cause downregulation of JNK-mediated signaling that promotes tumorigenesis. Here, we report a link between Hippo, IκBα and JNK signaling that may induce inflammation and innate immune response in tumorigenesis.

Hippo pathway was initially identified through genetic screens for genes regulating organ size in fruitflies. Recent studies have highlighted the role of Hippo signaling as a key regulator of homeostasis, and in tumorigenesis. Hippo pathway is comprised of genes that act as tumor suppressor genes like ( ) and ( ), and oncogenes like ( ). YAP and TAZ are two related mammalian homologs of Yki that act as effectors of the Hippo pathway. Hippo signaling deficiency can cause YAP- or TAZ-dependent oncogene addiction for cancer cells. YAP and TAZ are often activated in human malignant cancers. These transcriptional regulators may initiate tumorigenic changes in solid tumors by inducing cancer stem cells and proliferation, culminating in metastasis and chemo-resistance. Given the complex mechanisms (e.g., of the cancer microenvironment, and the extrinsic and intrinsic cues) that overpower YAP/TAZ inhibition, the molecular roles of the Hippo pathway in tumor growth and progression remain poorly defined. Here we review recent findings from studies in whole animal model organism like on the role of Hippo signaling regarding its connection to inflammation, tumor microenvironment, and other oncogenic signaling in cancer growth and progression.

Glioblastoma Multiforme (GBM) is the most common form of malignant brain tumor with poor prognosis. Amplification of Epidermal Growth Factor Receptor (EGFR), and mutations leading to activation of Phosphatidyl-Inositol-3 Kinase (PI3K) pathway are commonly associated with GBM. Using a previously published glioma model generated by coactivation of PI3K and EGFR pathways [by downregulation of Pten and overexpression of oncogenic Ras] in glial cells, we showed that the Tep1 gene (ortholog of human CD109) regulates Yki (the ortholog of human YAP/TAZ) via an evolutionarily conserved mechanism. Oncogenic signaling by the YAP/TAZ pathway occurs in cells that acquire CD109 expression in response to the inflammatory environment induced by radiation in clinically relevant models. Further, downregulation of Tep1 caused a reduction in Yki activity and reduced glioma growth. A key function of Yki in larval CNS is stem cell renewal and formation of neuroblasts. Other reports suggest different upstream regulators of Yki activity in the optic lobe versus the central brain regions of the larval CNS. We hypothesized that Tep1 interacts with the Hippo pathway effector Yki to regulate neuroblast numbers. We tested if Tep1 acts through Yki to affect glioma growth, and if in normal cells Tep1 affects neuroblast number and proliferation. Our data suggests that Tep1 affects Yki mediated stem cell renewal in glioma, as reduction of Tep significantly decreases the number of neuroblasts in glioma. Thus, we identify Tep1-Yki interaction in the larval CNS that plays a key role in glioma growth and progression.

Serogroup A of Neisseria meningitidis is the organism responsible for causing epidemic diseases in developing countries by a pilus-mediated adhesion to human brain endothelial cells. Type IV pilus assembly protein (PilF) associated with bacterial adhesion, aggregation, invasion, host cell signaling, surface motility, and natural transformation can be considered as a candidate for effective anti-meningococcal drug development. Since the crystal structure of PilF was not available, in the present study, it was modeled after the Z2491 strain (CAM09255.1) using crystal structure of chain A of Vibrio cholerae putative Ntpase EpsE (Protein Data Bank (PDB) ID: 1P9R) and then we based this analysis on sequence comparisons and structural similarity using in silico methods and docking processes, to design a suitable inhibitor molecule. The ligand 3-{(4S)-5-{[(1R)-1-cyclohexylethyl]amino}-4-[(5S)-5-(prop-2-en-1-yl) cyclopent-1-en-1-yl]-1,4-dihydro-7H-pyrrolo[2,3-d] pyrimidin-7-yl}-1,2-dideoxy-b-L-erythro-hex-1-en-3-ulofuranosyl binds to the protein with a binding energy of −8.10 kcal and showed a drug likeness of 0.952 with no predicted health hazard. It can be utilized as a potent inhibitor of N. meningitidis pilus-mediated adhesion to human brain endothelial cells preventing meningeal colonization.

The interaction between the tumor cells and the surrounding normal cells constitutes the Tumor microenvironment (TME). The Toll-like Receptor (TLR), Jun N-terminal Kinase (JNK), and Tumor Necrosis Factor (TNF) produce inflammatory components in the TME and are thought to play a critical role in tumor survival and progression. However, the exact nature and mechanism of interactions within the TME remain poorly understood. These core inflammatory pathways are conserved in Drosophila. As 90% of tumors are epithelial in origin, we used an epithelial tumor model in the wing imaginal discs of Drosophila melanogaster to study the interaction of these key inflammatory pathways in the TME. We established a new TME model by creating FLP-out clones of oncogenic forms of Yki or RasV12 in polarity deficient (scribble mutant) cells marked by GFP surrounded by normal cells. These mosaic clones allow us to test changes in intercellular and signaling interactions within the tumor, surrounding its microenvironment and in distant normal cells. We hypothesized that crosstalk between the TLR and TNF pathways in the TME promotes tumor survival and progression through JNK pathway. We observed Drosophila IκB Cactus (TLR component) is upregulated in the tumor cells and downregulating Cactus negatively affect tumor growth (JNK expression) and invasion (JNK target, MMP1 expression). The genetic epistasis experiments between JNK and TNF revealed that downregulation of the TNF receptors in the tumor does not affect the metastatic abilities of the tumor cells. Further, we report Hippo pathway effector, Yki as the ultimate regulator, that transcriptionally regulates Cactus expression which in turn mediates tumor promoting JNK signaling in the tumor cells.We also studied the tumorigenesis in the Drosophila glioma model generated by co-activation of the epidermal growth factor receptor (EGFR) and Phosphatidylinositol 3-kinase (PI3K) pathway. Glioma is an aggressive form of adult brain tumor with poor prognosis due to recurrence of tumor after surgery and radiation treatment. To understand the effect of radiation on glioma, we exposed the glioma to 3.5 Gy of X-ray and observed delayed growth, reduced brain lobe size, and proliferation, yet the exposed larvae did not have any survival advantage and were pupal lethal.Further, the recurrence of glioma after radiation has been associated with presence of glioma stem-like cells. Our collaborator, Dr. I Nakano’s group observed CD109 (Drosophila Tep1) protein is expressed by the surviving tumor cells after radiation treatment which transformed into aggressive and radioresistant tumor cells. Using mammalian and Drosophila models, we confirmed an evolutionarily conserved role of CD109 in glioma progression. Exposure of glioma to ionizing radiation led to transcription of CD109 by activated NF-κB and silencing of CD109 repressed transcription of TAZ. Downregulation of Tep1 in the Drosophila glioma model showed reduction in glioma size, proliferation and reduced Yki expression.Overall, our research helped to unravel the intricate interactions between key signaling pathways that promote tumor progression in an in vivo model. These insights can be extrapolated to mammalian system and further our understanding of tumorigenesis and designing new therapeutics.

Presence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved in Drosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We used Drosophila tumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms of Ras[V12] or its major effector Yorkie (Yki[3SA]) in polarity deficient cells mutant for tumor suppressor gene scribble (scrib) marked by GFP under nubGAL4 or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth of Yki[3SA] scrib[RNAi] or Ras[V12] scrib[RNAi] tumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated in Yki[3SA]scrib[RNAi] or Ras[V12]scrib[RNAi] tumors. Drosophila Cactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells. Competing Interest Statement The authors have declared no competing interest.

This study aimed to determine the correlation between pain perception and knowledge, attitude, and diet diversity in patients undergoing fixed orthodontic treatment. A total of 103 patients (15-40 yrs.; 67 females, 36 males) undergoing orthodontic treatment with a 0.022-inch slot (MBT prescription) in both arches were recruited. Information on pain perception, knowledge, attitude, and diet diversity scores was collected through validated questionnaires using visual analogue scale and close-ended questions at one time point. The correlation between variables was analyzed using the Pearson's correlation coefficient. Of the patients, 48.5% were aged 15 to 19 years old, with 65% females and 73.8% of Chinese ethnicity. Approximately 90% of the orthodontic patients perceived low levels of pain from orthodontic treatment, and 98% had a positive attitude toward orthodontic treatment. The patients had a good level of knowledge (Mean: 6±0.65). Approximately 49.5% of patients reported having moderate diet diversity. No significant correlation was found between pain perception and knowledge, or pain perception and diet diversity (r=0.062, p=0.534). However, a significant weak negative correlation (r=-0.289, p<0.05) between pain perception and attitude was observed. Patients undergoing fixed orthodontic treatment presented with overall low pain perception, a positive attitude, and good knowledge about their treatment with moderate diet diversity. Informing the patient in advance about different orthodontic procedures encourages a positive attitude and facilitates patient cooperation. An interprofessional approach involving nutritionists can provide a holistic patient approach during orthodontic treatment.