Despite recent efforts, prostate cancer (PCa) remains one of the most common cancers in men. Currently, there is no effective treatment for castration-resistant prostate cancer (CRPC). There is, therefore, an urgent need to identify new therapeutic targets. The Hippo pathway and its downstream effectors—the transcriptional co-activators, Yes-associated protein (YAP) and its paralog, transcriptional co-activator with PDZ-binding motif (TAZ)—are foremost regulators of stem cells and cancer biology. Defective Hippo pathway signaling and YAP/TAZ hyperactivation are common across various cancers. Here, we draw on insights learned from other types of cancers and review the latest advances linking the Hippo pathway and YAP/TAZ to PCa onset and progression. We examine the regulatory interaction between Hippo-YAP/TAZ and the androgen receptor (AR), as main regulators of PCa development, and how uncontrolled expression of YAP/TAZ drives castration resistance by inducing cellular stemness. Finally, we survey the potential therapeutic targeting of the Hippo pathway and YAP/TAZ to overcome PCa.

Effector T cells (TEFF) are a barrier to booster vaccination because they can rapidly kill Ag-bearing APCs before memory T cells are engaged. We report in this study that i.v. delivery of rhabdoviral vectors leads to direct infection of follicular B cells in the spleen, where the earliest evidence of secondary T cell responses was observed. This allows booster immunizations to rapidly expand CD8+ central memory T cells (TCM) during the acute phase of the primary response that is dominated by TEFF. Interestingly, although the ablation of B cells before boosting with rhabdoviral vectors diminishes the expansion of memory T cells, B cells do not present Ags directly. Instead, depletion of CD11c+ dendritic cells abrogates secondary T cell expansion, suggesting that virus-infected follicular B cells may function as an Ag source for local DCs to subsequently capture and present the Ag. Because TCM are located within B cell follicles in the spleen whereas TEFF cannot traffic through follicular regions, Ag production and presentation by follicular APCs represent a unique mechanism to secure engagement of TCM during an ongoing effector response. Our data offer insights into novel strategies for rapid expansion of CD8+ T cells using prime-boost vaccines by targeting privileged sites for Ag presentation.

Single-cell RNA-seq (scRNA-seq) studies have profiled over 100 million human cells across diseases, developmental stages, and perturbations to date. A singular view of this vast and growing expression landscape could help reveal novel associations between cell states and diseases, discover cell states in unexpected tissue contexts, and relatein vivocells toin vitromodels. However, these require a common, scalable representation of cell profiles from across the body, a general measure of their similarity, and an efficient way to query these data. Here, we present SCimilarity, a metric learning framework to learn and search a unified and interpretable representation that annotates cell types and instantaneously queries for a cell state across tens of millions of profiles. We demonstrate SCimilarity on a 22.7 million cell corpus assembled across 399 published scRNA-seq studies, showing accurate integration, annotation and querying. We experimentally validated SCimilarity by querying across tissues for a macrophage subset originally identified in interstitial lung disease, and showing that cells with similar profiles are found in other fibrotic diseases, tissues, and a 3D hydrogel system, which we then repurposed to yield this cell statein vitro. SCimilarity serves as a foundational model for single cell gene expression data and enables researchers to query for similar cellular states across the entire human body, providing a powerful tool for generating novel biological insights from the growing Human Cell Atlas.