Pan-cancer copy number variant analysis identifies optimized size thresholds and co-occurrence models for individualized risk-stratification.

Chromosome instability leading to accumulation of copy number gains or losses is a hallmark of cancer. Copy number variant (CNV) signatures are increasingly used for clinical risk-stratification, but size thresholds for defining CNVs are variable and the biological or clinical implications of CNV size heterogeneity or co-occurrence patterns are incompletely understood. Here we analyze CNV and clinical data from 565 meningiomas and 9,885 tumors from The Cancer Genome Atlas (TCGA) to develop tumor-and chromosome-specific CNV size-dependent and co-occurrence models for clinical outcomes. Our results reveal prognostic CNVs with optimized size thresholds and co-occurrence patterns that refine risk-stratification across a diversity of human cancers.

Hedgehog target genes regulate lipid metabolism to drive basal cell carcinoma and medulloblastoma.

Hedgehog (Hh) signaling is essential for development, homeostasis, and regeneration1. Misactivation of the Hh pathway underlies medulloblastoma, the most common malignant brain tumor in children, and basal cell carcinoma (BCC), the most common cancer in the United States2. Primary cilia regulate Hh signal transduction3, but target genes that drive cell fate decisions in response to ciliary ligands or oncogenic Hh signaling are incompletely understood. Here we define the Hh gene expression program using RNA sequencing of cultured cells treated with ciliary ligands, BCCs from humans, and Hh-associated medulloblastomas from humans and mice (Fig. 1a). To validate our results, we integrate lipidomic mass spectrometry and bacterial metabolite labeling of free sterols with genetic and pharmacologic approaches in cells and mice. Our results reveal novel Hh target genes such as the oxysterol synthase Hsd11ß1 and the adipokine Retnla that regulate lipid metabolism to drive cell fate decisions in response to Hh pathway activation. These data provide insights into cellular mechanisms underlying ciliary and oncogenic Hh signaling and elucidate targets to treat Hh-associated cancers.

NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy.

Meningiomas are the most common primary intracranial tumors1-3. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental4,5. Resistance to radiotherapy is common in high-grade meningiomas6, and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice. NOTCH3+ cells are restricted to the perivascular niche during meningeal development and homeostasis and in low-grade meningiomas but are expressed throughout high-grade meningiomas that are resistant to radiotherapy. Integrating single-cell transcriptomics with lineage tracing and imaging approaches across mouse genetic and xenograft models, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. An antibody stabilizing the extracellular negative regulatory region of NOTCH37,8 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. In summary, our results identify a conserved cell type and signaling mechanism that underlie meningioma tumorigenesis and resistance to radiotherapy, revealing a new therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

Spatial genomic, biochemical, and cellular mechanisms drive meningioma heterogeneity and evolution.

Intratumor heterogeneity underlies cancer evolution and treatment resistance1-5, but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all current medical therapies6,7. High-grade meningiomas cause significant neurological morbidity and mortality and are distinguished from low-grade meningiomas by increased intratumor heterogeneity arising from clonal evolution and divergence8. Here we integrate spatial transcriptomic and spatial protein profiling approaches across high-grade meningiomas to identify genomic, biochemical, and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal, and spatial evolution of cancer. We show divergent intratumor gene and protein expression programs distinguish high-grade meningiomas that are otherwise grouped together by current clinical classification systems. Analyses of matched pairs of primary and recurrent meningiomas reveal spatial expansion of sub-clonal copy number variants underlies treatment resistance. Multiplexed sequential immunofluorescence (seqIF) and spatial deconvolution of meningioma single-cell RNA sequencing show decreased immune infiltration, decreased MAPK signaling, increased PI3K-AKT signaling, and increased cell proliferation drive meningioma recurrence. To translate these findings to clinical practice, we use epigenetic editing and lineage tracing approaches in meningioma organoid models to identify new molecular therapy combinations that target intratumor heterogeneity and block tumor growth. Our results establish a foundation for personalized medical therapy to treat patients with high-grade meningiomas and provide a framework for understanding therapeutic vulnerabilities driving intratumor heterogeneity and tumor evolution.

Sociometric network analysis in illicit drugs research: A scoping review.

BACKGROUND: Sociometric or whole network analysis, a method used to analyze relational patterns among social actors, emphasizes the role of social structure in shaping behaviour. Such method has been applied to many aspects of illicit drug research, including in the areas of public health, epidemiology, and criminology. Previous reviews about social networks and drugs have lacked a focus on the use of sociometric network analysis for illicit drugs research across disciplines. The current scoping review aimed to provide an overview of the sociometric network analysis methods used in illicit drugs research and to assess how such methods could be used for future research. METHODS: A systematic search of six databases (Web of Science, ProQuest Sociology Collection, Political Science Complete, PubMed, Criminal Justice Abstracts, and PsycINFO) returned 72 relevant studies that met the inclusion criteria. To be included, studies had to mention illicit drugs and use whole social network analysis as one of their methods. Studies were summarized quantitatively and qualitatively using a data-charting form and a description of the studies' main topics. RESULTS: Sociometric network analysis in illicit drugs research has grown in popularity in the last decade, using mostly descriptive network metrics, such as degree centrality (72.2%) and density (44.4%). Studies were found to belong to three study domains. The first, drug crimes investigated network resilience and collaboration patterns in drug trafficking networks. The second domain, public health, focused on the social networks and social support of people who use drugs. Finally, the third domain focused on the collaboration networks of policy, law enforcement, and service providers. CONCLUSION: Future illicit drugs research using whole network SNA should include more diverse data sources and samples, incorporate mixed and qualitative methods, and apply social network analysis to study drug policy.

Total systems failure: police officers' perspectives on the impacts of the justice, health, and social service systems on people who use drugs.

BACKGROUND: Police in Canada have become main responders to behavioural health concerns in the community-a role that disproportionately harms people who use drugs (PWUD). Recent calls to defund the police emphasize the need to shift responsibility for non-criminal health issues from police to health and social services. This study explores the role of police interactions in responding to PWUD within the broader institutional and structural contexts in which they operate. METHODS: We conducted a qualitative thematic analysis of interviews with sixteen police officers across nine jurisdictions in British Columbia, Canada. We examined police officers' everyday policing experiences interacting with PWUD, enforcing drug laws, and working alongside other service sectors. RESULTS: Officers explained that the criminal justice system is one component of a wider network of systems that collectively fail to meet the needs of PWUD. They recognized that PWUD who interact with police often experienced intersecting structural vulnerabilities such as poverty, homelessness, and intergenerational trauma. Harmful drug laws in conjunction with inadequate treatment and housing resources contributed to a funnelling of PWUD into interactions with police. They provided several recommendations for reform including specialized health and justice roles, formalized intersectoral collaboration, and poverty reduction. CONCLUSIONS: Overall, this study provides unique insights into the positioning and role of police officers within a "total systems failure" that negatively impact PWUD. Police have become responders-by-default for issues that are fundamentally related to people's health conditions and socioeconomic circumstances. Addressing failures across the health, social, and justice systems to meet the needs of PWUD will require an examination of the shortcomings across these systems, as well as substantial funding and system reforms.

Simple possession as a 'tool': Drug law enforcement practices among police officers in the context of depenalization in British Columbia, Canada.

BACKGROUND: Examining drug law enforcement practices in the context of an evolving drug policy environment is critical for informing policy reforms and practices as they unfold. In this study, we aimed to examine police officer accounts of drug law enforcement practices, including officer use of discretion in simple possession cases, within the sociolegal context in British Columbia, Canada. METHODS: Using a qualitative approach, we conducted a thematic analysis of interviews with sixteen police officers across nine jurisdictions in the province. The analysis provided insights into police officers' recent experiences enforcing drug laws. Two major themes and several subthemes are presented which relate to drug law enforcement practices within the context of depenalization. FINDINGS: Officers' experiences and views towards simple possession enforcement suggested a model of de facto depenalization in the province, although enforcement practices including police discretion were inconsistent across officers and jurisdictions. Prosecutorial discretion was a major factor that shaped officers' enforcement practices. While officers reported not pursuing simple possession offences, many used simple possession charges as a 'tool' to do investigations, pursue other charges, and to promote social order. CONCLUSION: This study provides unique insights into drug law enforcement in an evolving sociolegal context, highlighting the potential inconsistencies, inequities, and harms that may arise from relying on a model of depenalization. In the face of drug law reforms both in Canada and elsewhere, these findings have important implications regarding the design and implementation of alternatives, such as depenalization, decriminalization, and diversion programs, which may potentially rely on, remove, and/or enhance police discretion. Where drug possession is formally decriminalized, police officers may need alternative enforcement 'tools' to support their work moving forward.