Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous largescale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.Cancer forms and progresses through a series of critical transitions-from pre-malignant to malignant states, from locally contained to metastatic disease, and from treatment-responsive to treatment-resistant tumors (Figure 1). Although specifics differ across tumor types and patients, all transitions involve complex dynamic interactions between diverse pre-malignant, malignant, and non-malignant cells (e.g., stroma cells and immune cells), often organized in specific patterns within the tumor

Summary Hutchinson-Gilford progeria syndrome (HGPS) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T, G608G) in LMNA , the nuclear lamin A gene. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid aging and shortens lifespan to ~14 years 1 – 4 . Adenine base editors (ABEs) perform targeted A•T-to-G•C base pair conversion with minimal byproducts and without requiring double-strand DNA breaks or donor DNA templates 5 , 6 . Here, we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured progeria patient-derived fibroblasts and in a mouse model of HGPS. Lentiviral delivery of ABE to patient-derived fibroblasts results in ~90% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced progerin levels, and correction of nuclear abnormalities. Unbiased off-target DNA and RNA analysis did not detect off-target editing activity in treated patient-derived fibroblasts. In transgenic mice homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (~20-60% across various organs 6 months post-injection), restoration of normal RNA splicing, and reduction of progerin protein. In vivo base editing rescued vascular pathology, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single ABE AAV9 injection at P14 improved animal vitality and greatly extended median lifespan from 215 to 510 days. These findings support the potential of in vivo base editing to treat HGPS, and other genetic diseases, by directly correcting the root cause of disease.

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by ll

IntroductionPulmonary arterial hypertension (PAH) is a life-limiting condition characterized by progressive vascular obliteration leading to right heart failure and ultimately death. Recent research has highlighted altered cellular and systemic metabolism as a key feature promoting pulmonary vascular disease and right heart BACKGROUND. Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose-and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS.Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS. PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulinsensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages.CONCLUSIONS. IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium-and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH.

The protein inference problem represents a major challenge in shotgun proteomics. In this article, we describe a novel Bayesian approach to address this challenge by incorporating the predicted peptide detectabilities as the prior probabilities of peptide identification. We propose a rigorious probabilistic model for protein inference and provide practical algoritmic solutions to this problem. We used a complex synthetic protein mixture to test our method and obtained promising results.