SummaryWnt signaling is a key regulator of development that is often associated with cancer. Wingless, a Drosophila Wnt homolog, has been reported to be a survival factor in wing imaginal discs. However, we found that prospective wing cells survive in the absence of Wingless as long as they are not surrounded by Wingless-responding cells. Moreover, local autonomous overactivation of Wg signaling (as a result of a mutation in APC or axin) leads to the elimination of surrounding normal cells. Therefore, relative differences in Wingless signaling lead to competitive cell interactions. This process does not involve Myc, a well-established cell competition factor. It does, however, require Notum, a conserved secreted feedback inhibitor of Wnt signaling. We suggest that Notum could amplify local differences in Wingless signaling, thus serving as an early trigger of Wg signaling-dependent competition.

SUMMARY A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting.

Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition. We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies. Sensitivity to binimetinib and ribociclib was inversely related ( = -0.58, = 0.009). amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs. Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS-MAPK signaling. .

†All authors contributed equally to this work.Endocytosis, with subsequent targeting to lysosomes for degradation, is traditionally seen as a way for cells to terminate signalling. However, in a few instances, endocytosis has been demonstrated to contribute positively to signalling. Here we review recent work on the role of endocytosis in Wnt signalling. Biochemical evidence suggests that the branch of Wnt signalling that controls planar cell polarity (PCP) does require endocytosis, although how endocytosis of Frizzled receptors is translated into PCP in vivo remains unknown. With respect to the main signalling branch (called the canonical or b-catenin pathway), the literature is divided as to whether endocytosis is required. Results of in vivo experiments are inconclusive because of the toxic side-effects of blocking endocytosis. Some results with cultured cells suggest the need for endocytosis in canonical signalling; however, it remains unclear whether the ligand-receptor complex must enter the cell by clathrin-mediated or caveolae-mediated endocytosis in order to signal. Means of specifically altering Wnt trafficking as well as of tracking the internalization route in different cell types are needed.