Pancreatic intraepithelial neoplasia (PanIN) is a premalignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance1. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53, and SMAD42-4. To date, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavor. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression in both genetic models and patient derived xenografts. Specifically, we developed Msi reporter mice that allowed image based tracking of stem cell signals within cancers, revealing that Msi expression rises as PanIN progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbor the capacity to propagate adenocarcinoma, are enriched in circulating tumor cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in PanIN progression to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumors, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumor penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signaling as a central regulator of pancreatic cancer.
Highlights d Map of PDAC dependencies using RNA-seq, ChIP-seq, and genome-wide CRISPR screening d Expression and direct utilization of cytokine and immune signals in PDAC stem cells d Nuclear hormone receptor RORg regulates mouse and human pancreatic cancer d Pharmacologic blockade of RORg reduces tumor burden and improves survival
How a single cell gives rise to an entire organism is one of biology's greatest mysteries. Within this process, stem cells play a key role by serving as seed cells capable of both self-renewal to sustain themselves as well as differentiation to generate the full diversity of mature cells and functional tissues. Understanding how this balance between self-renewal and differentiation is achieved is crucial to defining not only the underpinnings of normal development but also how its subversion can lead to cancer. Musashi, a family of RNA binding proteins discovered originally in Drosophila and named after the iconic samurai, Miyamoto Musashi, has emerged as a key signal that confers and protects the stem cell state across organisms. Here we explore the role of this signal in stem cells and how its reactivation can be a critical element in oncogenesis. Relative to long-established developmental signals such as Wnt, Hedgehog, and Notch, our understanding of Musashi remains in its infancy; yet all evidence suggests that Musashi will emerge as an equally powerful paradigm for regulating development and cancer and may be destined to have a great impact on biology and medicine.
With a cure rate of 95% in patients with HCV infection and ESRD Highlights Sofosbuvir/velpatasvir (SOF/VEL) is approved for patients with HCV infection. There is no dosing recommendation for SOF-based regimens for HCV-infected patients on dialysis. We evaluated SOF/VEL for 12 weeks in HCV-infected patients with end-stage renal disease on dialysis. SOF/VEL was safe and well tolerated, with a cure rate of 95% in our study.
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