Patterns of spindle orientationIn most epithelia, the common pattern of spindle orientation is planar, in which the spindle is aligned along the tissue plane, SummaryMitotic spindle orientation can influence tissue organization and vice versa. Cells orient their spindles by rotating them parallel or perpendicular to the cell -and hence the tissue -axis. Spindle orientation in turn controls the placement of daughter cells within a tissue, influencing tissue morphology. Recent findings implicating tumor suppressor proteins in spindle orientation bring to the forefront a connection between spindle misorientation and cancer. In this Commentary, we focus on the role of three major human tumor suppressors -adenomatous polyposis coli (APC), E-cadherin and von Hippel-Lindau (VHL) -in spindle orientation. We discuss how, in addition to their better-known functions, these proteins affect microtubule stability and cell polarity, and how their loss of function causes spindles to become misoriented. We also consider how other cancer-associated features, such as oncogene mutations, centrosome amplification and the tumor microenvironment, might influence spindle orientation. Finally, we speculate on the role of spindle misorientation in cancer development and progression. We conclude that spindle misorientation alone is unlikely to be tumorigenic, but it has the potential to synergize with cancer-associated changes to facilitate genomic instability, tissue disorganization, metastasis and expansion of cancer stem cell compartments. Journal of Cell Scienceparallel to the apical and basal surfaces of the cell (Fernández-Miñán et al., 2007; Fischer et al., 2006; Fleming et al., 2007;Lu et al., 2001) (Fig. 1). Planar spindle orientation leads to the establishment of a cytokinetic furrow that bisects the apical and basal cell surfaces, thereby generating daughter cells that are side by side in the tissue. Both daughter cells retain or re-establish contact with the extracellular matrix (ECM), and they attach to each other along their lateral surfaces (Jinguji and Ishikawa, 1992). Because daughter cells inherit identical contents and ECM attachments, planar spindle orientation can result in symmetric cell division ( Fig. 2A). Loss of planar orientation in tumors could disrupt epithelial tissue morphology by placing daughter cells one on top of the other, creating vertical tissue expansion.Although planar spindle orientation can result in symmetric cell division, it can also lead to asymmetric cell division. For example, in the developing mammalian brain, dividing cells can show planar spindle orientation, but partition cellular components -such as the apical surface and the basal process connecting it to the ECM, unequally -resulting in asymmetric cell division (Kosodo et al., 2004; Kosodo et al., 2008;Siller and Doe, 2009). Uneven distribution of microenvironmental factors, such as gradients of growth factors, could also influence the fates of daughter cells. This might be the case in intestinal crypts, where we found planar spindl...

SummaryOvarian cancer is the most lethal gynaecologic cancer, in large part because of its early dissemination and rapid development of chemotherapy resistance. Spheroids are clusters of tumor cells found in the peritoneal fluid of patients that are thought to promote this dissemination. Current models suggest that spheroids form by aggregation of single tumor cells shed from the primary tumor. Here, we demonstrate that spheroids can also form by budding directly as adherent clusters from a monolayer. Formation of budded spheroids correlated with expression of vimentin and lack of cortical E-cadherin. We also found that compared to cells grown in monolayers, cells grown as spheroids acquired progressive resistance to the chemotherapy drugs Paclitaxel and Cisplatin. This resistance could be completely reversed by dissociating the spheroids. Our observations highlight a previously unappreciated mode of spheroid formation that might have implications for tumor dissemination and chemotherapy resistance in patients, and suggest that this resistance might be reversed by spheroid dissociation.

Ovarian cancer has the highest mortality of all cancers of the female reproductive system. It accounts for three percent of all cancers in women and is the fifth leading cause of cancer-related death among women in the United States. Ovarian cancer cells can metastasize to the uterus, fallopian tubes, and pelvis tissues as well as to other organs. Even with optimal treatment there is a high probability that the cancer will recur, suggesting that current treatments are not successful in eliminating all of the ovarian cancer cells. This may be a result of a protective mechanism of the ovarian cancer cells. Spheroids are large collections of cancer cells that adhere tightly to each other rather than spreading out across an underlying basement membrane. They have been observed in ovarian cancer both in vivo and in ovarian cancer cell lines. Spheroids have been shown to play a role in the metastasis of ovarian cancer cells and have also been shown to be drug resistant. It is our hypothesis that spheroid formation results in epigenetic changes promoting the survival of ovarian cancer cells. Our data suggests that spheroid growth causes the growth rate of ovarian cancer cells to decrease and remain decreased following the transition from spheroids back to monolayer culture. Furthermore, serial passaging of ovarian cancer spheroids results in an increase in resistance to cytotoxic drugs. Since the decrease in growth rate appears to be persistent after spheroid culture it is likely the result of epigenetic modifications that occur during spheroid formation. These epigenetic changes, currently being studied, could become potential drug targets, as new treatments are developed to not only kill ovarian cancer cells but also prevent spheroid formation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1522. doi:10.1158/1538-7445.AM2011-1522