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In ovarian cancer, upregulation of the Wnt/&beta, &ndash, catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/&beta, catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked &beta, catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/&beta, catenin pathway are dependent on CD8+ T cells, we injected ID8 cells into mice with CD8+ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked &beta, catenin specifically in DCs. When CD8+ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment, a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/&beta, catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8+ T cells.

Summary: Here, we find that human-induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (CM)-fated progenitors (CFPs) that express a tetraspanin family glycoprotein, CD82, almost exclusively differentiate into CMs both in vitro and in vivo. CD82 is transiently expressed in late-stage mesoderm cells during hiPSC differentiation. Purified CD82+ cells gave rise to CMs under nonspecific in vitro culture conditions with serum, as well as in vivo after transplantation to the subrenal space or injured hearts in mice, indicating that CD82 successfully marks CFPs. CD82 overexpression in mesoderm cells as well as in undifferentiated hiPSCs increased the secretion of exosomes containing β-catenin and reduced nuclear β-catenin protein, suggesting that CD82 is involved in fated restriction to CMs through Wnt signaling inhibition. This study may contribute to the understanding of CM differentiation mechanisms and to cardiac regeneration strategies. : Takeda et al. find that CD82+ is a cell-surface marker on cardiomyocyte-fated progenitors made from human iPSCs. Keywords: iPSCs, CD82, cardiomyocytes, progenitors, exosome, Wnt inhibition

SUMMARY Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders., In Brief Nehme et al. combine two strong neuralizing factors (transcription factor programming and small molecule patterning) to generate human excitatory neurons from stem cells. They further undertake single-cell and reporter gene approaches to select highly differentiated neurons with increased functionality, augmenting their utility in the modeling of nervous system disorders.

Objective: Glioma Stem Cells (GSCs) are considered to be responsible for dismal prognosis of Glioblastoma (GBM). WNT signaling is one of the major players in GSCs that promotes their radio- and chemoresistance. In this study we tested whether LGK974, an inhibitor of both canonical and non-canonical [for full text, please go to the a.m. URL], 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Cancer stem cells (CSCs), also known as tumor initiating cells are now considered to be the root cause of most if not all cancers, evading treatment and giving rise to disease relapse. They have become a central focus in new drug development. Prospective identification, understanding the key pathways that maintain CSCs, and being able to target CSCs, particularly if the normal stem cell population could be spared, could offer an incredible therapeutic advantage. The Wnt signaling cascade is critically important in stem cell biology, both in homeostatic maintenance of tissues and organs through their respective somatic stem cells and in the CSC/tumor initiating cell population. Aberrant Wnt signaling is associated with a wide array of tumor types. Therefore, the ability to safely target the Wnt signaling pathway offers enormous promise to target CSCs. However, just like the sword of Damocles, significant risks and concerns regarding targeting such a critical pathway in normal stem cell maintenance and tissue homeostasis remain ever present. With this in mind, we review recent efforts in modulating the Wnt signaling cascade and critically analyze therapeutic approaches at various stages of development.

Aberrant regulation of Wnt signaling is a common theme seen across many tumor types. Decades of research have unraveled the epigenetic and genetic alterations that result in elevated Wnt pathway activity. More recently, it has become apparent that Wnt signaling levels identify stem-like tumor cells that are responsible for fueling tumor growth. As therapeutic targeting of these tumor stem cells is an intense area of investigation, a concise understanding on how Wnt activity relates to cancer stem cell traits is needed. This review attempts at summarizing the intricacies between Wnt signaling and cancer stem cell biology with a special emphasis on colorectal cancer.