ACSM6 overexpression indicates a non-inflammatory tumor microenvironment and predicts treatment response in bladder cancer: results from multiple real-world cohorts.

Background: ACSMs play critical roles in lipid metabolism; however, their immunological function within the tumor microenvironment (TME) remains unclear, especially that of ACSM6. In this study, we investigate the latent effect of ACSM6 on bladder cancer (BLCA). Methods: Several real-world cohorts, including the Xiangya (in-house), The Cancer Genome Atlas (TCGA-BLCA), and IMvigor210 cohorts, with TCGA-BLCA cohort serving as the discovery cohort were compared. We investigated the potential immunological effects of ACSM6 in regulating the BLCA tumor microenvironment by analyzing its correlation with immunomodulators, anti-cancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, we assessed the precision of ACSM6 in predicting BLCA molecular subtypes and responses to several treatments using ROC analysis. To ensure the robustness of our findings, all results were confirmed in two independent external cohorts: the IMvigor210 and Xiangya cohorts. Results: ACSM6 expression was markedly upregulated in BLCA. Our analysis suggests that ACSM6 might have significant impact to promote the formation of a non-inflamed tumor microenvironment because of its negative correlation with immunomodulators, anticancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, high ACSM6 expression levels in BLCA may predict the luminal subtype, which is typically associated with resistance to chemotherapy, neoadjuvant chemotherapy, and radiotherapy. These findings were consistent across both the IMvigor210 and Xiangya cohorts. Conclusion: ACSM6 has the potential to serve as a valuable predictor of the tumor microenvironment phenotypes and treatment outcomes in BLCA, thereby contributing to more precise treatment.

GATA3 Predicts the Tumor Microenvironment Phenotypes and Molecular Subtypes for Bladder Carcinoma.

Aims: GATA3 is a key player in antitumor immunology, and continuous studies show that it might be a key biomarker for bladder cancer (BLCA). Thus, we lucubrate the immunological role of GATA3 in BLCA. Main Methods: We initially used pan-cancer analysis to analyze the expression pattern and immunological function of GATA3 with data gathered from the TCGA (The Cancer Genome Atlas). Then, in the BLCA tumor microenvironment (TME), we comprehensively associated GATA3 with immunomodulators, cancer immune cycles, tumor-infiltrating immune cells (TIICs), immune checkpoints, and T-cell inflamed scores(TIS). The role of GATA3 in predicting BLCA molecular subtypes and responsiveness to various treatment regimens was also investigated. We confirmed our findings in an external cohort and the Xiangya-Pingkuang cohort to guarantee the correctness of our study. Key Findings: GATA3 was preferentially expressed in the TME of numerous malignancies, including BLCA. High GATA3 expression was adversely connected with immunological aspects such as immunomodulators, cancer immune cycles, TIICs, immune checkpoints, and TIS in the BLCA TME. In addition, high GATA3 was more likely to be a luminal subtype, which meant it was less susceptible to cancer immunotherapy and neoadjuvant chemotherapy but more sensitive to targeted treatments. Significance: GATA3 may aid in the precision treatment for BLCA because it can accurately predict the clinical outcomes and the TME characteristics of BLCA.

Discovery of potent and selective Bcl-2 inhibitors with acyl sulfonamide skeleton.

The antiapoptotic protein B-cell lymphoma 2 (Bcl-2), overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, a series of novel derivatives with acyl sulfonamide skeleton was designed, synthesized, and evaluated as Bcl-2 inhibitors by means of bioisosteric replacement. Among them, compound 24g demonstrated equal efficient inhibition activity against RS4;11 cell line compared to positive control ABT-199. Moreover, it showed improved selectivity for Bcl-2/Bcl-xL inhibitory effects, the result of which was consistent with platelet toxicity studies. In vitro and in vivo pharmacokinetic properties of compound 24g had a significantly improved profiles. Taken together, those results suggested it as a promising candidate for development of novel therapeutics targeting Bcl-2 in cancer.

A Novel TGF-ß Risk Score Predicts the Clinical Outcomes and Tumour Microenvironment Phenotypes in Bladder Cancer.

Background: The TGF-ß pathway plays critical roles in numerous malignancies. Nevertheless, its potential role in prognosis prediction and regulating tumour microenvironment (TME) characteristics require further elucidation in bladder cancer (BLCA). Methods: TGF-ß-related genes were comprehensively summarized from several databases. The TCGA-BLCA cohort (training cohort) was downloaded from the Cancer Genome Atlas, and the independent validation cohorts were gathered from Xiangya Hospital (Xinagya cohort) and Gene Expression Omnibus. Initially, we identified differentially expressed TGF-ß genes (DEGs) between cancer and normal tissues. Subsequently, univariate Cox analysis was applied to identify prognostic DEGs, which were further used to develop the TGF-ß risk score by performing LASSO and multivariate Cox analyses. Then, we studied the role of the TGF-ß risk score in predicting prognosis and the TME phenotypes. In addition, the role of the TGF-ß risk score in guiding precision treatments for BLCA has also been assessed. Results: We successfully constructed a TGF-ß risk score with an independent prognostic prediction value. A high TGF-ß risk score indicated an inflamed TME, which was supported by the positive relationships between the risk score, enrichment scores of anticancer immunity steps, and the infiltration levels of tumour-infiltrating immune cells. In addition, the risk score positively correlated with the expression of several immune checkpoints and the T cell inflamed score. Consistently, the risk score was positively related to the enrichment scores of most immunotherapy-positive pathways. In addition, the sensitivities of six common chemotherapeutic drugs were positively associated with the risk score. Furthermore, higher risk score indicated higher sensitivity to radiotherapy and EGFR-targeted therapy. On the contrary, patients with low-risk scores were more sensitive to targeted therapies, including the blockade of FGFR3 and WNT-ß-catenin networks. Conclusions: We first constructed and validated a TGF-ß signature that could predict the prognosis and TME phenotypes for BLCA. More importantly, the TGF-ß risk score could aid in individual precision treatment for BLCA.