A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.

Pericytes conceivably play important roles in the tumour microenvironment of glioblastoma multiforme (GBM) by allowing for an aberrant vasculature and acting as a component in the perivascular niche that supports glioma stem‐like cells. However, a lack of specific markers has hampered in‐depth elucidation of the functional contribution of pericytes to GBM. This study provides a comprehensive computational biology approach to annotate pericyte marker genes in the GBM vasculature through integration of data from single‐cell RNA‐sequencing studies of both mouse and human tissue, as well as bulk tumour and healthy tissue gene expression data from patients with GBM. We identified distinct vascular‐ and immune‐related gene expression programmes in tumour pericytes that we assessed for association with GBM characteristics and patient survival. Most compellingly, pericyte gene signatures that were upregulated in tumours compared with normal brain tissue were indicative of progression of low‐grade gliomas into high‐grade glioma, suggested by a markedly shorter overall survival. Our results underline the functional importance of tumour pericytes in low‐grade glioma and may serve as a starting point for efforts for precision targeting of pericytes.

Metastatic breast cancer is responsible for most breast cancer-related deaths. Disseminated cancer cells have developed an intrinsic ability to resist anchorage-dependent apoptosis (anoikis). Anoikis is caused by the absence of cellular adhesion, a process that underpins lumen formation and maintenance during mammary gland development and homeostasis. In healthy cells, anoikis is mostly governed by B-cell lymphoma-2 (BCL2) protein family members. Metastatic cancer cells, however, have often developed autocrine BCL2-dependent resistance mechanisms to counteract anoikis. In this Review, we discuss how a pro-apoptotic subgroup of the BCL2 protein family, known as the BH3-only proteins, controls apoptosis and anoikis during mammary gland homeostasis and to what extent their inhibition confers tumor suppressive functions in metastatic breast cancer. Specifically, the role of the two pro-apoptotic BH3-only proteins BCL2-modifying factor (BMF) and BCL2-interacting mediator of cell death (BIM) will be discussed here. We assess current developments in treatment that focus on mimicking the function of the BH3-only proteins to induce apoptosis, and consider their applicability to restore normal apoptotic responses in anchorage-independent disseminating tumor cells.

Background: Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through clinical positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. Methods: In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome, exome, transcriptome, and imaging analyses. Results: Our findings unveil that hypermetabolic lesions, originating from hypometabolic lesions, exhibit strategic focal amplifications and deletions, and heightened APOBEC3 activity. Furthermore, we identify dipeptidase 1 as a novel vascular endothelial tip marker for hypermetabolic lesions in glioblastoma, facilitating angiogenesis and tumor metabolism by regulating transporter activities. Conclusions: Hypermetabolic lesions are associated with a higher frequency of genomic abnormalities and dipeptidase 1 emerges as a novel diagnostic and prognostic vascular marker for hypermetabolic lesions. This study underscores a spatial genomic evolution with diagnostic implications and elucidates challenges and opportunities crucial for the development of novel therapeutic strategies.