RNA-binding proteins (RBPs) are key players in post-transcriptional events. The combination of versatility of their RNA-binding domains with structural flexibility enables RBPs to control the metabolism of a large array of transcripts. Perturbations in RBP–RNA networks activity have been causally associated with cancer development, but the rational framework describing these contributions remains fragmented. We review here the evidence that RBPs modulate multiple cancer traits, emphasize their functional diversity, and assess future trends in the study of RBPs in cancer.

RNA-Binding Proteins in Cancer: Old Players and New Actors

Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance

The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.

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The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer.

Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas.

The epithelial mesenchymal transition (EMT) plays a central role in both normal physiological events (e.g., embryonic development) and abnormal pathological events (e.g., tumor formation and metastasis). The processes that occur in embryonic development are often reactivated under pathological conditions such as oncogenesis. Therefore, defining the regulatory networks (both gene and protein levels) involved in the EMT during embryonic development will be fundamental in understanding the regulatory networks involved in tumor development, as well as metastasis. There are many molecules, factors, mediators and signaling pathways that are involved in the EMT process. Although the EMT is a very old topic with numerous publications, recent new technologies and discoveries give this research area some new perspective and direction. It is now clear that these important processes are controlled by a network of transcriptional and translational regulators in addition to post-transcriptional and post-translational modifications that amplify the initial signals. In this review article, we will discuss some key concepts, historical findings, as well as some recent progresses in the EMT research field.

Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview.

Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ijc.29642

A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells.

3D bioprinting is an emerging biofabrication strategy using bioinks, comprising cells and biocompatible materials, to produce functional tissue models. Despite progress in building increasingly complex objects, biological analyses in printed constructs remain challenging. Especially, methods that allow non-invasive and non-destructive evaluation of embedded cells are largely missing. Here, we implemented Raman imaging for molecular-sensitive investigations on bioprinted objects. Different aspects such as culture formats (2D, 3D-cast, and 3D-printed), cell types (endothelial cells and fibroblasts), and the selection of the biopolymer (alginate, alginate/nanofibrillated cellulose, alginate/gelatin) were considered and evaluated. Raman imaging allowed for marker-independent identification and localization of subcellular components against the surrounding biomaterial background. Furthermore, single-cell analysis of spectral signatures, performed by multivariate analysis, demonstrated discrimination between endothelial cells and fibroblasts and identified cellular features influenced by the bioprinting process. In summary, Raman imaging was successfully established to analyze cells in 3D culture in situ and evaluate them with regard to the localization of different cell types and their molecular phenotype as a valuable tool for quality control of bioprinted objects.

Jessica Pfannstiel

Papers

A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells.

Non-Invasive Three-Dimensional Cell Analysis in Bioinks by Raman Imaging