SummaryThe peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Sara Suliman is an assistant professor in the Department of Experimental Medicine at the University of California, San Francisco (UCSF). Her lab uses multiple approaches to identify candidate tuberculosis (TB) risk pathways and to determine their role in TB progression. I caught up with Sara to talk about how she got interested in science, what she’s currently working on, and what she thinks about the future of academic science.

In this Viewpoint, we hear from a cross section of women, across multiple research fields, discussing their science and the process of setting up a lab as an independent researcher. As well as being able to celebrate the positives of becoming an independent researcher, we would also like to use this platform to discuss the unique challenges they face as women scientists in their respective scientific environments.

<p>Supplementary Table 1 and Supplmentary Figures 1-3 Legends</p>

<p>CELSR3 is a target for T-cell redirection therapeutics. <b>A,</b> CELSR3xCD3 bs-mAb directs T-cell mediated cytotoxicity in CELSR3(+) TCCSUP NLR and PM154 NLR but not CELSR3(−) DU145 NLR, TCCSUP CELSR3 KO cell lines. 5:1 (exp. 1) or 10:1 (exp. 2) pan T cells to tumor cells were added to each well along with CELSR3xCD3 bs-mAb and imaged using the IncuCyte S3 platform. Maximum cell lysis occurred by day 7 timepoint. At least three biological replicates were analyzed from one independent experiment. <b>B,</b> Cell surface expression of CELSR3 on tumor cell lines determined by quantitative flow cytometry and calculated from at least 10,000 events per sample. Dotted line denotes assay lower limit of detection.</p>

<div><p>Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration <i>in vitro</i>. We provide <i>in vivo</i> data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC.</p>Significance:<p>The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.</p></div>

<p>Supplementary Figure 2. Percentage of RHAMM positive cells that were detected using IHC in the indicate tumor type or benign prostate tissue.</p>