Phagocytic monocyte-derived macrophages associate with the nodes of Ranvier and initiate demyelination while microglia clear debris and display a suppressed metabolic gene signature in EAE.

Recently developed spatial gene expression technologies such as the SpatialTranscriptomics and Visium platforms allow for comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing methods for analyzing spatial gene expression data often do not efficiently leverage the spatial information and fail to address the limited resolution of the technology. Here, we introduce BayesSpace, a fully Bayesian statistical method for clustering analysis and resolution enhancement of spatial transcriptomics data that seamlessly integrates into current transcriptomics analysis workflows. We show that BayesSpace improves the identification of transcriptionally distinct tissues from spatial transcriptomics samples of the brain, of melanoma, and of squamous cell carcinoma. In particular, BayesSpace's improved resolution allows the identification of tissue structure that is not detectable at the original resolution and thus not recovered by other methods. Using an in silico dataset constructed from scRNA-seq, we demonstrate that BayesSpace can spatially resolve expression patterns to near single-cell resolution without the need for external single-cell sequencing data.In all, our results illustrate the utility BayesSpace has in facilitating the discovery of biological insights from a variety of spatial transcriptomics datasets.

Tumourigenesis is a multistep process that results from the sequential accumulation of mutations in key oncogene and tumour suppressor pathways. Personalized cancer therapy that is based on targeting these underlying genetic abnormalities presupposes that sustained inactivation of tumour suppressors and activation of oncogenes is essential in advanced cancers. Mutations in the p53 tumour-suppressor pathway are common in human cancer and significant efforts toward pharmaceutical reactivation of defective p53 pathways are underway1–3. Here we show that restoration of p53 in established murine lung tumours leads to significant but incomplete tumour cell loss specifically in malignant adenocarcinomas but not in adenomas. We define amplification of MAPK signaling as a critical determinant of malignant progression and also a stimulator of Arf tumour-suppressor expression. The response to p53 restoration in this context is critically dependent on the expression of Arf. We propose that p53 not only limits malignant progression by suppressing the acquisition of alterations that lead to tumour progression, but also, in the context of p53 restoration, responds to increased oncogenic signaling to mediate tumor regression. Our observations also underscore that the p53 pathway is not engaged by low levels of oncogene activity that are sufficient for early stages of lung tumour development. These data suggest that restoration of pathways important in tumour progression, as opposed to initiation, may lead to incomplete tumour regression due to the stage-heterogeneity of tumour cell populations.