RAB11A and RAB11B control mitotic spindle function in intestinal epithelial progenitor cells.

RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues.

Rab8 attenuates Wnt signaling and is required for mesenchymal differentiation into adipocytes.

Differentiation of mesenchymal stem cells into adipocyte requires coordination of external stimuli and depends upon the functionality of the primary cilium. The Rab8 small GTPases are regulators of intracellular transport of membrane-bound structural and signaling cargo. However, the physiological contribution of the intrinsic trafficking network controlled by Rab8 to mesenchymal tissue differentiation has not been fully defined in vivo and in primary tissue cultures. Here, we show that mouse embryonic fibroblasts (MEFs) lacking Rab8 have severely impaired adipocyte differentiation in vivo and ex vivo. Immunofluorescent localization and biochemical analyses of Rab8a-deficient, Rab8b-deficient, and Rab8a and Rab8b double-deficient MEFs revealed that Rab8 controls the Lrp6 vesicular compartment, clearance of basal signalosome, traffic of frizzled two receptor, and thereby a proper attenuation of Wnt signaling in differentiating MEFs. Upon induction of adipogenesis program, Rab8a- and Rab8b-deficient MEFs exhibited severely defective lipid-droplet formation and abnormal cilia morphology, despite overall intact cilia growth and ciliary cargo transport. Our results suggest that intracellular Rab8 traffic regulates induction of adipogenesis via proper positioning of Wnt receptors for signaling control in mesenchymal cells.

Gaining insight into the supportive care needs of women experiencing gynaecological cancer: A qualitative study.

AIM AND OBJECTIVES: To gain insight into the supportive care needs of Western Australian women experiencing gynaecological cancer. BACKGROUND: Meeting the supportive care needs of people living with cancer is becoming increasingly important as advances in cancer treatment contribute to growing numbers of survivors. International evidence suggests between 24%-56% of women with gynaecological cancer have unmet supportive care needs and that psychological challenges, information provision and holistic care are priorities. No qualitative investigation has previously explored women's journey of gynaecological cancer within the Australian setting. DESIGN: A qualitative descriptive design was used. METHODS: Women treated for gynaecological cancer were recruited from a tertiary public women's hospital in Western Australia. Thematic analysis was conducted on qualitative data collected from 190 women over 12 months through written open-ended survey responses and telephone interviews. The COnsolidated criteria for REporting Qualitative research (COREQ) guided presentation of results. RESULTS: Analysis yielded five themes and four subthemes: (a) Communication style directs the experience (subthemes: feeling supported; absence of empathy); (b) It's not just about the disease (subthemes: life has changed; holistic care); (c) A desire for information; (d) Drawing upon resilience; and (e) Navigating the system. DISCUSSION: Exploration of the women's needs leads to the discussion of three concepts. Communication styles, harnessing women's resilience and alternative models of care are evaluated for their capacity to improve care and women's quality of life into survivorship. Recommendations are made for further research and possible interventions that can be translated into the clinical setting. CONCLUSION: Women with gynaecological cancer described complex often unmet supportive care needs and interactions with the healthcare system. Insight gained directs suggestions for improved service provision. RELEVANCE TO CLINICAL PRACTICE: Improved patient-centred communication, harnessing resilience as a resource and alternative models of care for follow-up are encouraged as areas of improvement for clinicians and care services.

Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling.

The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, whereas suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. SIGNIFICANCE: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.

The supportive care needs of women experiencing gynaecological cancer: a Western Australian cross-sectional study.

BACKGROUND: Women diagnosed with gynaecological cancer experience supportive care needs that require care provision to reduce the impact on their lives. International evidence suggests supportive care needs of women with gynaecological cancer are not being met and provision of holistic care is a priority area for action. Knowledge on gynaecological cancer supportive care needs is limited, specifically comparison of needs and cancer gynaecological subtype. Our aim was to identify supportive care needs of Western Australian women experiencing gynaecological cancer, their satisfaction with help and explore associations between participant's demographic characteristics and identified needs. METHODS: A cross-sectional design incorporating a modified version of the Supportive Care Needs Survey - short form (SCNS-SF34) assessed 37 supportive care needs under five domains in conjunction with demographic data. Three hundred and forty three women with gynaecological cancer attending a tertiary public referral hospital completed the survey over 12 months. Statistical analysis was performed using the R environment for statistical computing. A linear regression model was fitted with factor scores for each domain and demographic characteristics as explanatory variables. RESULTS: Three hundred and three women (83%) identified at least one moderate or high level supportive care need. The five highest ranked needs were, 'being informed about your test results as soon as feasible' (54.8%), 'fears about cancer spreading' (53.7%), 'being treated like a person not just another case' (51.9%), 'being informed about cancer which is under control or diminishing (that is, remission)' (50.7%), and 'being adequately informed about the benefits and side-effects of treatments before you choose to have them' (49.9%). Eight of the top ten needs were from the 'health system and information' domain. Associations between supportive care items and demographic variables revealed 'cancer type', and 'time since completion of treatment' had no impact on level of perceived need for any domain. CONCLUSIONS: Western Australian women with gynaecological cancer identified a high level of supportive care needs. The implementation of a supportive care screening tool is recommended to ensure needs are identified and care is patient-centred. Early identification and management of needs may help to reduce the burden on health system resources for managing ongoing needs.