Song Wu

Purpose: Bladder cancer (BCa), particularly NMIBC, poses a substantial clinical burden due to its high recurrence rates and the need for lifelong surveillance. While large-scale studies have identified systemic metabolic risk signatures, a critical gap remains in understanding the dynamic, pre-diagnostic evolution of the metabolome and how these systemic alterations relate to early tumor metabolic reprogramming. To address this gap, we used a large prospective cohort with multi-omics data to characterize pre-diagnostic metabolic changes and their links to early tumor metabolic alterations in BCa. Experimental Design: Baseline plasma metabolomics from 48,241 controls and 2,158 BCa cases in the UK Biobank were analyzed to characterize metabolic alterations preceding diagnosis. Targeted metabolomics and transcriptomics were performed in an independent clinical cohort of 107 NMIBC patients and 56 controls. An eight-metabolite plasma classification model was developed and internally validated. Multi-omics integration and functional experiments were conducted to investigate the role of butyrate. Results: 64 circulating metabolites were associated with future BCa risk, predominantly involving lipid and lipoprotein metabolism. Targeted metabolomics identified 24 differential metabolites, including elevated butyric acid and maleic acid in NMIBC. An eight-metabolite plasma panel achieved an area under the receiver operating characteristic curve (AUC) of 0.98 in the held-out test and 0.92 in the validation set, with cross-biofluid validation in urine yielding an AUC of 0.75. Mechanistically, butyrate remodeled chromatin accessibility and activated AP-1 associated transcriptional programs linked to urothelial phenotypic plasticity. Conclusions: These findings define lipid dysregulation as a hallmark of the pre-diagnostic metabolic landscape of BCa.

Bladder cancer (BCa) progression is driven by complex interactions within the tumor microenvironment, yet the underlying multicellular communication networks remain poorly defined. Here, we integrated bulk, single‐cell, and spatial transcriptomic data with multiplexed immunofluorescence to construct a comprehensive cellular atlas across normal urothelium, precancerous lesions, and progressive BCa. We identified a stemness‐associated malignant epithelial population (Cluster 1_SDC1), a prognostically unfavorable subset of POSTN+ myofibroblastic cancer‐associated fibroblasts (mCAFs), and immunosuppressive monocytic myeloid‐derived suppressor cells (M‐MDSCs), all enriched in high‐grade tumors. Spatial mapping revealed a coordinated signaling cascade wherein POSTN+ mCAFs and M‐MDSCs co‐localize and engage integrin α5β1 on tip endothelial cells through FN1 and NAMPT, collectively driving angiogenesis. In turn, tip endothelial cells reinforce tumor stemness through downstream COL4A1/2–SDC1 signaling. Therapeutically, targeting integrin α5β1 with RGD peptide suppressed tumor growth and vascularization, while its combination with hydrogel‐based delivery and immune checkpoint blockade elicited broad‐spectrum antitumor responses. These findings uncover a spatially coordinated immune–stroma–tumor signaling cascade and establish integrin α5β1 as a central therapeutic target, providing a rationale for stroma‐directed combination strategies in progressive BCa.

Psoriasis is a recurrent autoimmune disease. No biological factor that is associated with the risk of psoriasis has been definitively identified. The potential role of the immunogen double‐stranded (ds)DNA as a trigger of and biomarker for psoriasis warrants exploration. This multicentre case–control study included 3 069 patients with psoriasis and 7 041 healthy controls from 12 regions in China. The associations of the serum dsDNA level with the psoriasis risk and severity were analysed in the overall population. The serum dsDNA level was significantly higher in patients than in controls. Each 0.1 ng/mL increase in serum dsDNA was significantly associated with increased odds of psoriasis (adjusted odds ratio, 1.45; 95% confidence interval, 1.40–1.48; p < 0.001). The optimal serum dsDNA cutoff value for the diagnosis of psoriasis was 1.11 ng/mL, with 61.6% sensitivity and 74.8% specificity. A significant dose–response relationship was observed between the serum dsDNA level and the risk of psoriasis‐associated morbidity when using the optimal dsDNA cutoff value as the reference. Serum dsDNA levels were positively associated with higher PASI and BSA scores and the severity of psoriasis. These findings suggest that serum dsDNA level is strongly associated with psoriasis morbidity and severity.

Cancer relapse upon chemotherapy remains the primary challenge in cancer treatment. By integrating high-resolution CRISPR/Cas9-based evolving lineage tracing with single-cell RNA sequencing in mice, we track the evolution of bladder carcinoma in the presence or absence of chemotherapy. We find that a cell population exhibiting an epidermoid-like cell state can survives chemotherapy. These epidermoid-like cells leave the quiescent state to initiate relapse, generating histologically distinct tumours through different evolutionary routes involving specific transcriptional changes. The plasticity of epidermoid-like cells and alterations in plasticity patterns during evolution shape the phenotypes of relapsed tumours. Integrated analyses reveal that Insulin-like growth factor-binding protein 5 is a key co-regulator of aggressive progression and squamous features in bladder carcinoma. Impeding insulin-like growth factor-binding protein 5 expression suppresses the chemoresistance and malignant behaviours of relapsed tumours. Our study deciphers key events and evolutionary dynamics during the natural progression and recurrence of bladder carcinoma. It offers a viable therapeutic approach to overcome the refractoriness of relapsed bladder carcinoma to conventional chemotherapy.