Snail1 is a central regulator of epithelial cell adhesion and movement in epithelial‐to‐mesenchymal transitions (EMTs) during embryo development; a process reactivated during cancer metastasis. While induction of Snail1 transcription precedes EMT induction, post‐translational regulation of Snail1 is also critical for determining Snail1's protein level, subcellular localization, and capacity to induce EMT. To identify novel post‐translational regulators of Snail1, we developed a live cell, bioluminescence‐based screen. From a human kinome RNAi screen, we have identified Lats2 kinase as a novel regulator of Snail1 protein level, subcellular localization, and thus, activity. We show that Lats2 interacts with Snail1 and directly phosphorylates Snail1 at residue T203. This occurs in the nucleus and serves to retain Snail1 in the nucleus thereby enhancing its stability. Lats2 was found to positively influence cellular EMT and tumour cell invasion, in a Snail1‐dependent manner. Indeed during TGFβ‐induced EMT Lats2 is activated and Snail1 phosphorylated at T203. Analysis in mouse and zebrafish embryo development confirms that Lats2 acts as a positive modulator of Snail1 protein level and potentiates its in vivo EMT activity.

Metastasis and tumor progression are the major cause of death in patients suffering from pancreatic ductal adenocarcinoma. Tumor growth and especially dissemination are typically associated with activation of an epithelial-to-mesenchymal transition (EMT) program. This phenotypic transition from an epithelial to a mesenchymal state promotes migration and survival both during development and in cancer progression. When re-activated in pathological contexts such as cancer, this type of developmental process confers additional stemness properties to specific subsets of cells. Cancer stem cells (CSCs) are a subpopulation of cancer cells with stem-like features that are responsible for the propagation of the tumor as well as therapy resistance and cancer relapse, but also for circulating tumor cell release and metastasis. In support of this concept, EMT transcription factors generate cells with stem cell properties and mediate chemoresistance. However, their role in pancreatic ductal adenocarcinoma metastasis remains controversial. As such, a better characterization of CSC populations will be crucial in future development of therapies targeting these cells. In this review, we will discuss the latest updates on the mechanisms common to pancreas development and CSC-mediated tumor progression.

During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata, and genomics, we found that sphingosine-1-phosphate (S1p), signalling through the G protein coupled receptor (GPCR) S1pr2, plays a key role in pancreas development linking lineage allocation and specification. S1pr2 signalling promotes progenitor survival as well as acinar and endocrine specification. S1pr2-mediated stabilisation of the yes-associated protein (YAP) is essential for endocrine specification, thus linking a regulator of progenitor growth with specification. YAP stabilisation and endocrine cell specification rely on G_αi subunits, revealing an unexpected specificity of selected GPCR intracellular signalling components. Finally, we found that S1pr2 signalling posttranscriptionally attenuates Notch signalling levels, thus regulating lineage allocation. Both S1pr2-mediated YAP stabilisation and Notch attenuation are necessary for the specification of the endocrine lineage. These findings identify S1p signalling as a novel key pathway coordinating cell survival, lineage allocation, and specification and linking these processes by regulating YAP levels and Notch signalling. Understanding lineage allocation and specification in the pancreas will shed light in the origins of pancreatic diseases and may suggest novel therapeutic approaches. The pancreas develops from a field of progenitor cells localised in a restricted region of the embryonic endoderm. These progenitor cells proliferate and eventually differentiate to generate the three distinct lineages comprising the endocrine (which include insulin-producing β cells), acinar, and ductal cells. The molecular pathways implicated in the early generation of pancreas progenitors and their proliferation are well understood. It is also known that the Notch signalling pathway is implicated in sequential binary cell fate decisions that generate the three lineages; however, other signals that may regulate this process remain unknown. Here, we show that a phospholipid, sphingosine-1-phosphate (S1p), generated by the progenitor cells themselves, acts as a signal necessary to define the acinar and endocrine lineage. We observe that in the absence of S1p only duct cells are generated and the survival of pancreas progenitors is compromised. The function of this signalling pathway in the generation of the endocrine cells is two-fold. Firstly, it stabilises yes-associated protein (YAP), a transcriptional gene coactivator known to regulate pancreatic progenitor proliferation, and we show that this stability is necessary for the activation of the endocrine specification program. Secondly, it attenuates Notch signalling, allowing the generation of endocrine and acinar cells. Notch attenuation is necessary for the stabilisation of the transcription factor Ngn3, which is required for the generation of endocrine cells. We conclude that S1p acts as an autocrine signal regulating YAP stabilisation and Notch attenuation to mediate pancreas specification. Understanding lineage allocation and specification in the pancreas will shed light on the origins of pancreatic diseases and may suggest novel therapeutic approaches.

During the development of the nervous system the regulation of cell cycle, differentiation, and survival is tightly interlinked. Newly generated neurons must keep cell cycle components under strict control, as cell cycle re-entry leads to neuronal degeneration and death. However, despite their relevance, the mechanisms controlling this process remain largely unexplored. Here we show that Scratch2 is involved in the control of the cell cycle in neurons in the developing spinal cord of the zebrafish embryo.scratch2knockdown induces postmitotic neurons to re-enter mitosis. Scratch2 prevents cell cycle re-entry by maintaining high levels of the cycle inhibitor p57 through the downregulation of miR-25. Thus, Scratch2 appears to safeguard the homeostasis of postmitotic primary neurons by preventing cell cycle re-entry.

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.