Background Cancer stem-like cells drive tumor progression and therapeutic resistance, yet the epithelial stemness hierarchy in bladder cancer (BLCA) remains poorly defined. We aimed to characterize stemness-associated epithelial populations and their clinical significance. Methods We analyzed single-cell RNA sequencing data from 92,218 cells across 13 treatment-naïve BLCA samples to characterize epithelial stemness and tumor–microenvironment interactions. Spatial transcriptomics and independent bulk cohorts were used for orthogonal and clinical validation. An HStem-associated histopathology-based prognostic model was developed by integrating quantitative image features with deep-learning representations, followed by functional validation of the candidate gene C11orf24. Results We identified a highly stem-like epithelial population (HStem) at the apex of the differentiation hierarchy, exhibiting MYC activation, oxidative phosphorylation, and DNA repair enrichment, with preferential presence in advanced-stage tumors. HStem cells were inferred to serve as major communication hubs within the TME, interacting extensively with fibroblasts and endothelial cells via MIF–CD74/CXCR4 and MIF–CD74/CD44 axes. An 86-gene HStem signature enabled development of a robust image-based prognostic model. High-risk tumors showed immune exclusion, immunosuppressive enrichment, T-cell dysfunction, and predicted checkpoint blockade resistance. C11orf24 emerged as a candidate stemness-associated regulator; C11orf24-positive cells displayed enhanced stemness and stromal interactions. Functional experiments demonstrated that C11orf24 perturbation altered clonogenic growth, migration, and invasion in BLCA cells. Pharmacogenomic analyses identified predicted therapeutic vulnerabilities that warrant experimental validation. Conclusions We identify an HStem population associated with BLCA progression, microenvironmental remodeling, and immune evasion. Integrating single-cell and spatial transcriptomics with computational pathology, we establish a clinically relevant stemness framework and identify C11orf24 as a potential therapeutic target, offering opportunities for stemness-directed precision oncology.
Background Surgery remains standard treatment for localized renal cancer. Whether partial nephrectomy (PN), compared with radical nephrectomy (RN), affects long-term cardiovascular disease-specific mortality (CVD-SM) in stage II disease is uncertain. We assessed this association using competing-risk methods. Methods Patients with T2N0M0 renal cancer diagnosed in the SEER database from 2004 to 2022 were included. Missing tumor grade and unspecified T2 subclassification were addressed by multiple imputation. Propensity-score matching was performed within 10 imputed datasets. Cumulative incidence functions were estimated using the Aalen–Johansen method. Fine–Gray models were primary, with cause-specific Cox models as supportive analyses; estimates were pooled across imputations. Results The cohort included 14,602 patients (PN, n = 1294; RN, n = 13,308), with a median follow-up of 85 months. After matching, 1290–1292 patients per group were retained. Five-year CVD-SM cumulative incidence was 2.68% after PN and 3.07% after RN; 10-year estimates were 7.18% and 6.63%, respectively. No significant association was observed (Fine–Gray sHR, 1.10; 95% CI, 0.69–1.74; P = 0.690; Cox HR, 1.04; 95% CI, 0.66–1.64; P = 0.867). PN was associated with lower cancer-specific mortality (Fine–Gray sHR, 0.58; 95% CI, 0.42–0.80; P < 0.001). Conclusion Among patients with stage II renal cancer, surgical approach was not significantly associated with CVD-SM. However, estimate imprecision and unavailable cardiovascular and renal risk factors preclude claims of equivalence or exclusion of clinically meaningful effects. The potential cardiovascular benefit of PN remains uncertain. Its lower cancer-specific mortality should be interpreted cautiously because residual surgical-selection confounding may persist. Synopsis Cardiovascular disease-specific mortality represents an important long-term competing risk in patients with stage II renal cancer. No statistically significant association between surgical approach and cardiovascular disease-specific mortality was detected, leaving the cardiovascular survival advantage of partial nephrectomy uncertain.
Background Colorectal cancer liver metastasis (CRLM) is a major cause of mortality in colorectal cancer (CRC) and develops within a heterogeneous tumor microenvironment (TME). How immune, stromal, and metabolic programs differ between primary CRC and matched liver metastases remains incompletely resolved. Methods We analyzed publicly available single-cell RNA sequencing (scRNA-seq) data from GSE178318 (15 specimens from six patients: six primary CRC samples, six matched liver metastases, and three peripheral-blood mononuclear cell samples) together with bulk RNA-seq data from GSE50760 (54 samples from 18 patients spanning normal colon, primary CRC, and liver metastasis). The single-cell workflow included quality control, score-based cell-type annotation, patient-level pseudobulk differential expression, pathway/module scoring, ligand-receptor co-expression analysis, and diffusion-map pseudotime. Bulk data were assessed using within-patient paired comparisons, co-expression analysis, and program-level scoring. Benjamini-Hochberg false-discovery-rate (FDR) correction was applied for multiple testing. Results After quality control, 132,915 single cells were retained. Liver metastases showed higher patient-level T/NK-cell fractions and lower malignant epithelial and B/plasma-cell fractions than primary tumors. In paired single-cell pseudobulk analysis, no gene remained significant at the prespecified FDR threshold, although nominal differences suggested extracellular-matrix and metabolic changes. Glycolysis scores were modestly higher and oxidative-phosphorylation scores modestly lower in liver metastases, whereas inflammatory and glycolytic scores were not correlated at the patient-tissue level. Ligand-receptor co-expression was strongest for MIF-CD74, VIM-CD44, and HLA-A-CD8A, with CAF/stromal and myeloid/TAM populations showing high aggregate outgoing scores. Diffusion pseudotime showed increasing EMT/invasion scores and decreasing glycolysis along the inferred transcriptomic ordering; this ordering is descriptive and not a longitudinal lineage. In the bulk cohort, 654 genes differed between liver metastasis and primary tumor, while cross-platform rank concordance was weak (Spearman rho=0.106). Conclusions Public single-cell and bulk datasets support compartment-associated differences in cellular composition and transcriptional programs in CRLM, with prominent stromal, myeloid, and metabolic features. However, limited patient numbers, cross-sectional sampling, weak cross-platform concordance, and the absence of experimental validation mean that the ligand-receptor and trajectory findings should be interpreted as hypothesis-generating rather than causal or clinically validated.
Methionine sulfoxide reductase B3 (MSRB3) possesses potent antioxidant activity and is highly expressed in various cancers, often correlating with poor prognosis. However, its biological effect and clinical importance in gastric cancer (GC) remain elusive. In this study, we first validated the expression and prognostic value of MSRB3 in GC through bioinformatics analyzes and clinical specimens. Subsequently, a series of functional experiments in vitro and in vivo were executed to explore the effect of MSRB3 in regulating GC cell proliferation, invasion, migration, ferroptosis, and the tumor immune microenvironment, as well as the underlying mechanisms. Finally, a subcutaneous xenograft model was established to assess the influence of MSRB3 on tumor growth and the efficacy of anti-PD-1 therapy. MSRB3 was markedly elevated in GC, and linked to poor patient prognosis. Functionally, MSRB3 facilitated the growth, migration, and invasion of GC cells. Indeed, MSRB3 stabilized GPX4 protein by inhibiting its ubiquitin-proteasomal-degradation, thereby suppressing lipid peroxidation and ferroptosis, which sustained GC cell survival and malignant progression. In vivo experiments confirmed that MSRB3 promoted tumor growth by inhibiting ferroptosis. Moreover, loss of MSRB3 increased intratumoral CD8⁺ T-cell accumulation and significantly enhanced the therapeutic response to PD-1 blockade. This synergy was reversed via the ferroptosis inhibitor Ferrostatin-1. MSRB3 functions as a suppressor of ferroptosis in GC by preserving GPX4 protein stability. MSRB3 drives tumor progression and confers immunotherapy resistance by stabilizing GPX4 to inhibit ferroptosis. Therefore, targeting MSRB3 may represent a potential strategy to improve immunotherapeutic efficacy in GC.
Hypoxia-driven epigenetic remodeling is a critical determinant of lung adenocarcinoma (LUAD) progression and therapeutic resistance, yet the epigenetic mechanisms coordinating hypoxia signaling with tumor microenvironment remodeling remain incompletely understood. Here, by integrating LUAD cell models, murine tumor models, and spatial transcriptomics with reference-based cell-type deconvolution, we identify SATB2 as a previously unrecognized hypoxia-inducible epigenetic regulator in LUAD. HIF-1α, unlike HIF-2α, directly interacts with the promoter of SATB2, promoting its expression in hypoxic environments. Increased levels of SATB2 have been linked to more severe clinical and pathological characteristics as well as poorer outcomes for patients. Mechanistically, SATB2 physically interacts with HIF-1α and p300, while SATB2 loss reduces H3K27 acetylation and elongating RNA polymerase II occupancy at HIF-1 target loci, supporting a model in which SATB2 facilitates HIF-1α-dependent transcriptional elongation and establishes a positive feedback circuit that amplifies hypoxia-responsive transcriptional programs. Spatial transcriptomic analyses further show that SATB2-associated hypoxic programs are preferentially enriched within malignant tumor niches and are associated with remodeling of the local tumor microenvironment. Functionally, SATB2 promotes LUAD growth, metastasis, angiogenesis, and bevacizumab resistance in a HIF-1α-dependent manner, whereas genetic disruption of SATB2 or pharmacological inhibition of p300 enhances sensitivity to anti-angiogenic therapy. Collectively, these findings identify the SATB2–p300–HIF-1α axis as a hypoxia-responsive epigenetic regulatory mechanism linking transcriptional adaptation to malignant progression and resistance to anti-angiogenic therapy, and provide a preclinical rationale for further investigation of this pathway as a potential therapeutic vulnerability in LUAD.
