Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.

The development of optically tunable and intensely scattering materials is of wide interest in biophotonics and medicine, provided they are biocompatible. Highly linear, tunable, narrow-gap, and intensely scattering gold nanobead chains were prepared by a green synthesis scheme, starting from ultrapure gold nanosphere monomers having a virgin surface. These Au nanochains exhibit a tunable longitudinal surface plasmon resonance (SPR) over the range from 590 to 710 nm. To determine the ensemble statistics of the synthesized nanobead chain lengths and their branching, transmission electron microscopy (TEM) images were acquired, in batch, correlated with the nanochain longitudinal SPR maxima (590 to 640 nm). Monte Carlo simulations quantify the selectivity of the chemical reaction: chain-end gold nanosphere units are about 4 times more reactive than chain-center units and assemble under a high-inverse-order-dependent diffusion. Discrete dipole approximation (DDA) computations predict the experimental extinction spectra and the narrow gap distance of the chains, as well as the elongated chain’s optical scattering enhancement, relative to Au nanosphere monomers (approximately 3× enhancement at equivalent mass). In vitro dark-field microscopy, cell studies, and biocompatibility tests demonstrate the nanochains’ (1) intense optical scattering cross sections, related to the plasmon coupling between the constituent nanospheres, (2) highly accessible gold surfaces, enabling facile conjugation with cell targeting ligands, and (3) absence of cell toxicity. The herein reported scalable, green synthesized, readily conjugatable gold nanobead chains are thus of great potential utility for serving as a wide range of biophotonic platforms, such as for enhanced in vitro and in vivo contrast imaging, diagnostics, and targeted nanotheranostics.

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