Background: Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations.

We have shown previously that mutations in the apico-basal cell polarity regulators cooperate with oncogenic Ras (Ras ACT ) to promote tumorigenesis in Drosophila melanogaster and mammalian cells. To identify novel genes that cooperate with Ras ACT in tumorigenesis, we carried out a genome-wide screen for genes that when overexpressed throughout the developing Drosophila eye enhance Ras ACT -driven hyperplasia. Ras ACT -cooperating genes identified were Rac1 Rho1, RhoGEF2, pbl, rib, and east, which encode cell morphology regulators. In a clonal setting, which reveals genes conferring a competitive advantage over wildtype cells, only Rac1, an activated allele of Rho1 (Rho1 ACT ), RhoGEF2, and pbl cooperated with Ras ACT , resulting in reduced differentiation and large invasive tumors. Expression of RhoGEF2 or Rac1 with Ras ACT upregulated Jun kinase ( JNK) activity, and JNK upregulation was essential for cooperation. However, in the whole-tissue system, upregulation of JNK alone was not sufficient for cooperation with Ras ACT , while in the clonal setting, JNK upregulation was sufficient for Ras ACT -mediated tumorigenesis. JNK upregulation was also sufficient to confer invasive growth of Ras V12 -expressing mammalian MCF10A breast epithelial cells. Consistent with this, HER2 1 human breast cancers (where human epidermal growth factor 2 is overexpressed and Ras signaling upregulated) show a significant correlation with a signature representing JNK pathway activation. Moreover, our genetic analysis in Drosophila revealed that Rho1 and Rac are important for the cooperation of RhoGEF2 or Pbl overexpression and of mutants in polarity regulators, Dlg and aPKC, with Ras ACT in the whole-tissue context. Collectively our analysis reveals the importance of the RhoGEF/ Rho-family/JNK pathway in cooperative tumorigenesis with Ras ACT .

The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state.

Background: Consumer engagement in clinical research is increasingly being prioritized by major funders such as the Australian National Health and Medical Research Council. Methods: We performed a systematic literature search of the Cochrane library, Embase, CINAHL PubMed and Medline to identify randomized clinical trials in surgery with perioperative outcomes conducted in Australia. All publications underwent review and thematic analysis to identify levels of consumer engagement and the inclusion of patient-reported outcome measures (PROMS). Results: From 5373 records, the full texts of 809 articles were retrieved, of which 41 clinical trials met the inclusion criteria. PROMS were identified in 63% of the trials as a primary or secondary outcome. Despite multiple available checklists and analysis tools, less than 2% of studies documented any consumer engagement apart from PROMS. Conclusion: There was very little consumer engagement in formulation, management, conduct and dissemination of the trial findings.'integrated, planned, and personalised approach to patient care before, during, and after any surgical procedure involving anaesthesia '. 11 Consumer engagement should assist these aims.For medical research, there are (often mandatory) growing requirements to incorporate the consumer encompassing the patient, patient's family or carer into all steps of the process, from identification of the research question, trial management, document writing, dissemination and translation of the results. 3,12,13 Although the adoption of consumer engagement is relevant and justifiable, experience to date suggests increasing expense and mostly 'tokenistic' approaches. 14 It is unclear what best practice approaches or evaluation methods are available or should be used. [15][16][17] Medical research includes both quantitative and qualitative approaches, mainly focusing on endpoints and/or outcomes that are perceived to benefit the patient (consumer). 17,18 In Australia, there has been no review to date identifying consumer engagement in perioperative medicine research or to classify or define the levels and types of consumer engagement. In 1996, the UK National Institute of Health Research established and funded an INVOLVE supporting the National Health Service to include and understand the consumer perspective. 19 The supporting statement of INVOLVE is 'research being carried out 'with' or 'by' members of the public rather than "to", "about" or "for" them'. 19 Patient-reported outcome measures