Inactivation of Aurora kinases and Cyclin-dependent kinases 4/6 allows cancers to adopt an endoreplication and form polyploid/polyaneuploid giant cancer cells (PGCCs/PACCs) that resist antimitotic drugs

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Lgl1 controls NG2 endocytic pathway to regulate oligodendrocyte differentiation and asymmetric cell division and gliomagenesis.

Oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division (ACD) to generate one OPC and one differentiating oligodendrocyte (OL) progeny. Loss of pro-mitotic proteoglycan and OPC marker NG2 in the OL progeny is the earliest immunophenotypic change of unknown mechanism that indicates differentiation commitment. Here, we report that expression of the mouse homolog of Drosophila tumor suppressor Lethal giant larvae 1 (Lgl1) is induced during OL differentiation. Lgl1 conditional knockout OPC progeny retain NG2 and show reduced OL differentiation, while undergoing more symmetric self-renewing divisions at the expense of asymmetric divisions. Moreover, Lgl1 and hemizygous Ink4a/Arf knockouts in OPC synergistically induce gliomagenesis. Time lapse and total internal reflection microscopy reveals a critical role for Lgl1 in NG2 endocytic routing and links aberrant NG2 recycling to failed differentiation. These data establish Lgl1 as a suppressor of gliomagenesis and positive regulator of asymmetric division and differentiation in the healthy and demyelinated murine brain

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma

Virtual alignment of pathology image series for multi-gigapixel whole slide images

Abstract Interest in spatial omics is on the rise, but generation of highly multiplexed images remains challenging, due to cost, expertise, methodical constraints, and access to technology. An alternative approach is to register collections of whole slide images (WSI), generating spatially aligned datasets. WSI registration is a two-part problem, the first being the alignment itself and the second the application of transformations to huge multi-gigapixel images. To address both challenges, we developed Virtual Alignment of pathoLogy Image Series (VALIS), software which enables generation of highly multiplexed images by aligning any number of brightfield and/or immunofluorescent WSI, the results of which can be saved in the ome.tiff format. Benchmarking using publicly available datasets indicates VALIS provides state-of-the-art accuracy in WSI registration and 3D reconstruction. Leveraging existing open-source software tools, VALIS is written in Python, providing a free, fast, scalable, robust, and easy-to-use pipeline for registering multi-gigapixel WSI, facilitating downstream spatial analyses

Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma