PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk.

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of STAT3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial cross-talk as a potential novel target in PDAC treatment. Cancer Res; 77(8); 1868-79. ©2017 AACR.

New insights in the development of pancreatic cancer.

PURPOSE OF REVIEW: The review intends to describe recent studies on the development of pancreatic cancer from a genetic, molecular, and microenvironment perspective. RECENT FINDINGS: Pancreatic cancer has been discovered to have distinct molecular subtypes based on transcriptome analyses that may have implications for treatment. Recent studies are also mapping the complex molecular biology of this cancer as it relates to the core signaling abnormalities inherent to this disease. There have been discoveries of novel modes of regulation of pancreatic cancer development, including alterations in key transcription factors, epigenetic modifiers, and metabolic pathways. Studies of the tumor-associated microenvironment continue to reveal its complex role in tumor development. SUMMARY: Pancreatic cancer development appears to depend on a multifaceted network of signals that are dynamic, involve multiple cell types, and are linked to spatiotemporal factors in tumor evolution. Understanding the development of pancreatic cancer in this context is key to identifying novel and effective targets for treatment.

Phosphorylation of p40AUF1 regulates binding to A + U-rich mRNA-destabilizing elements and protein-induced changes in ribonucleoprotein structure.

Messenger RNA turnover directed by A + U-rich elements (AREs) involves selected ARE-binding proteins. Whereas several signaling systems may modulate ARE-directed mRNA decay and/or post-translationally modify specific trans-acting factors, it is unclear how these mechanisms are linked. In THP-1 monocytic leukemia cells, phorbol ester-induced stabilization of some mRNAs containing AREs was accompanied by dephosphorylation of Ser83 and Ser87 of polysome-associated p40AUF1. Here, we report that phosphorylation of p40AUF1 influences its ARE-binding affinity as well as the RNA conformational dynamics and global structure of the p40AUF1-ARE ribonucleoprotein complex. Most notably, association of unphosphorylated p40AUF1 induces a condensed RNA conformation upon ARE substrates. By contrast, phosphorylation of p40AUF1 at Ser83 and Ser87 inhibits this RNA structural transition. These data indicate that selective AUF1 phosphorylation may regulate ARE-directed mRNA turnover by remodeling local RNA structures, thus potentially altering the presentation of RNA and/or protein determinants involved in subsequent trans-factor recruitment.