Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.
Four studies explored the motivational and experiential dynamics of psychological needs, applying both self-determination theory and motive disposition theory. In all 4 studies, motive dispositions toward achievement and affiliation ("wanting" particular experiences) predicted corresponding feelings of competence and relatedness ("having" those experiences). Competence and relatedness in turn predicted well-being, again indicating that these 2 experiences may really be "needed." Illuminating how wanting gets to having, in Studies 2 and 3, participants reported greater self-concordance for motive-congruent goals, which, in longitudinal Study 3, predicted greater attainment of those goals and thus enhanced well-being. Study 4 replicated selected earlier results using an implicit as well as an explicit motive disposition measure. Supporting the presumed universality of competence and relatedness needs, in no studies did motive dispositions moderate the effects of corresponding need-satisfaction on well-being. Discussion focuses on a "sequential process" model of psychological needs that views needs as both motives that instigate and outcomes that reward behavior.
Epithelial organoids are simplified models of organs grown in vitro from embryonic and adult stem cells. They are widely used to study organ development and disease, and enable drug screening in patient-derived primary tissues. Current protocols, however, rely on animal- and tumor-derived basement membrane extract (BME) as a 3D scaffold, which limits possible applications in regenerative medicine. This prompted us to study how organoids interact with their matrix, and to develop a well-defined hydrogel that supports organoid generation and growth. It is found that soft fibrin matrices provide suitable physical support, and that naturally occurring Arg-Gly-Asp (RGD) adhesion domains on the scaffold, as well as supplementation with laminin-111, are key parameters required for robust organoid formation and expansion. The possibility to functionalize fibrin via factor XIII-mediated anchoring also allows to covalently link fluorescent nanoparticles to the matrix for 3D traction force microscopy. These measurements suggest that the morphogenesis of budding intestinal organoids results from internal pressure combined with higher cell contractility in the regions containing differentiated cells compared to the regions containing stem cells. Since the fibrin/laminin matrix supports long-term expansion of all tested murine and human epithelial organoids, this hydrogel can be widely used as a defined equivalent to BME.
Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.
a b s t r a c tSelf determination theory (SDT) proposes that all humans have a need for competence. But is this need modulated by individual differences? Our research integrated SDT, which defines psychological needs (including competence) as universally essential experiences, and motive disposition theories, which define psychological needs as individually varying non conscious motives. A cross sectional and a longi tudinal study showed that felt competence in a sports activity has especially positive effects on subse quent flow and intrinsic motivation for individuals high in the need for achievement. Study 3 showed that felt competence more strongly influences subsequent academic goal motivation for those high in the need for achievement. Discussion focuses on the importance of integrating universalist and individual difference approaches to motivation, to derive the most complete understanding.
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