Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities.

Disabled cell density sensing leads to dysregulated cholesterol synthesis in glioblastoma

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRβ to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRβ, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRβ gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRβ regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRβ in glioblastoma might be effective through diverse mechanisms.

Case report of a HER2-expressed ovarian clear cell carcinoma with exceptional response to trastuzumab deruxtecan.

The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. In this study, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA sequencing [RNA-seq; The Cancer Genome Atlas (TCGA)], single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and single-sample gene set enrichment analysis. Key findings were validated using digital spatial profiling and IHC. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, with highest observed in prostate adenocarcinoma. Genes significantly correlated with AR activity showed negative associations and were enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFNγ pathway activity across tumors and sexes—unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed that AR inhibition enhanced immune cell and IFNγ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex. Significance: Tumor-associated AR activity negatively correlates with immune infiltration and immunotherapy response across cancers, independent of sex, suggesting that combining AR inhibitors with checkpoint blockade may benefit patients with immunotherapy-refractory tumors.