Prostate cancer is the second leading cause of male cancer death in the U.S. Current immune checkpoint inhibitor–based immunotherapies have improved survival for many malignancies; however, they have failed to prolong survival for prostate cancer. Siglecs (sialic acid–binding immunoglobulin-like lectins) are expressed on immune cells and regulate their function. Siglec-7 and Siglec-9 contribute to immune evasion in cancer by interacting with sialic acid–containing glycoprotein ligands on cancer cells. However, the role of Siglec-7/9 receptors and their ligands in prostate cancer remains poorly understood. Here, we find that Siglec-7 and Siglec-9 are associated with poor prognosis in patients with prostate cancer and are highly expressed in myeloid cells, including macrophages, in prostate tumor tissues. Siglec-7 and -9 ligands were expressed in prostate cancer cells and human prostate tumor tissues. Blocking the interactions between Siglec-7/9 and sialic acids inhibited prostate cancer xenograft growth and increased immune cell infiltration in humanized mice in vivo. Using a CRISPRi screen and mass spectrometry, we identified CD59 as a candidate Siglec-9 ligand in prostate cancer. The identification of Siglec-7 and -9 as potential therapeutic targets, including the CD59/Siglec-9 axis, opens up opportunities for immune-based interventions in prostate cancer.

Millions of ribosomes are packed within mammalian cells, yet we lack tools to visualize them in toto and characterize their subcellular composition. In this study, we present ribosome expansion microscopy (RiboExM) to visualize individual ribosomes and an optogenetic proximity-labeling technique (ALIBi) to probe their composition. We generated a super-resolution ribosomal map, revealing subcellular translational hotspots and enrichment of 60 S subunits near polysomes at the endoplasmic reticulum (ER). We found that Lsg1 tethers 60 S to the ER and regulates translation of select proteins. Additionally, we discovered ribosome heterogeneity at mitochondria guiding translation of metabolism-related transcripts. Lastly, we visualized ribosomes in neurons, revealing a dynamic switch between monosomes and polysomes in neuronal translation. Together, these approaches enable exploration of ribosomal localization and composition at unprecedented resolution.

Dermal interstitial fluid (ISF) offers a promising alternative to invasive blood tests and opportunities for skin diagnostics. Progress in both the understanding and adoption of ISF tests is hindered by sampling challenges, including lengthy collection times, non-negligible failure rates, variable collection volumes, and inconsistent bioanalyte levels. The causes of many of these issues are not well understood. We demonstrate a microneedle device that is several times faster than state of the art, collecting an average of 15.5 mg of ISF in 5 minutes in humans with near-zero failure rate. This improvement was achieved by designing the spatial pressure gradient driving ISF flow. The influence of penetration depth, collection time, pressure, and age on ISF collection was elucidated, with Darcy’s law explaining multiple observations. A data-driven acceptance criterion of <1% blood contamination for ISF is proposed. The device and findings presented will empower researchers to better conduct robust studies in the development of ISF diagnostics.

Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE ₂ ) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.

Metastasis is the main cause of prostate cancer–associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as tumor-associated calcium signal transducer 2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. Although shed TECD did not affect prostate cancer cell proliferation and tumor growth, it increased cell migration and invasion in vitro and promoted metastatic colonization and spontaneous metastasis in vivo. TECD interactome and proteomic studies revealed that TECD binds to EGFR and shed TECD modulates a set of proteins associated with invasion, migration, mTOR signaling, and epithelial-to-mesenchymal transition. Furthermore, elevated shed TECD increased EGFR phosphorylation, resulting in the activation of the EGFR–PI3K–AKT–mTOR pathway in prostate cancer. EGFR inhibitors suppressed the invasive ability of prostate cancer cells driven by TECD overexpression, further supporting the key role of EGFR in TECD-mediated prostate cancer progression. This study uncovers a function of TECD in driving prostate cancer progression and provides mechanistic insights into TECD signaling through EGFR. Significance: Shed extracellular domain of TROP2 binds to and activates EGFR and stimulates the PI3K-AKT-mTOR signaling cascade to promote prostate cancer metastasis, providing potential biomarkers and therapeutic targets.

Background: Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck that is highly prevalent in Southeast Asia and North Africa. Though an extensive analysis of environmental and genetic contributors has been performed, very little is known about the proteome of this disease. A proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissues can provide valuable information on protein expression and molecular patterns for both increasing our understanding of the disease and for biomarker discovery. To date, very few NPC proteomic studies have been performed, and none focused on patients from Morocco and North Africa. Methods: Label-free Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) was used to perform a proteomic analysis of FFPE tissue samples from a cohort of 41 NPC tumor samples of Morocco and North Africa origins. The LC-MS/MS data from this cohort were analyzed alongside 21 healthy controls using MaxQuant 2.4.2.0. A differential expression analysis was performed using the MSstats package in R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations were carried out using the DAVID bioinformatic tool. Results: 3341 proteins were identified across our NPC cases, revealing three main clusters and five DEPs with prognostic significance. The sex disparity of NPC was investigated from a proteomic perspective in which 59 DEPs were found between males and females, with significantly enriched terms associated with the immune response and gene expression. Furthermore, 26 DEPs were observed between patients with early and advanced stages of NPC with a significant cluster related to the immune response, implicating up-regulated DEPs such as IGHA, IGKC, and VAT1. Across both datasets, 6532 proteins were quantified between NPC patients and healthy controls. Among them, 1507 differentially expressed proteins (DEPs) were observed. GO and KEGG pathway analyses showed enriched terms of DEPs related to increased cellular activity, cell proliferation, and survival. PI3K and MAPK proteins as well as RAC1 BCL2 and PPIA were found to be overexpressed between cancer tissues and healthy controls. EBV infection was also one of the enriched pathways implicating its latent genes like LMP1 and LMP2 that activate several proteins and signaling pathways including NF-Kappa B, MAPK, and JAK-STAT pathways. Conclusion: Our findings unveil the proteomic landscape of NPC for the first time in the Moroccan population. These studies additionally may provide a foundation for identifying potential biomarkers. Further research is still needed to help develop tools for the early diagnosis and treatment of NPC in Moroccan and North African populations.