Molecular vasculogenic mimicry–Related signatures predict clinical outcomes and therapeutic responses in bladder cancer: Results from real-world cohorts

Abstract

Bladder cancer (BLCA) is a heterogeneous disease, and there are many classical molecular subtypes that reflect tumor immune microenvironment (TME) heterogeneity but their clinical utility is limited and correct individual treatment and prognosis cannot be predicted based on them. To find reliable and effective biomarkers and tools for predicting patients’ clinical responses to several therapies, we developed a new systemic indicator of molecular vasculogenic mimicry (VM)–related genes mediated by molecular subtypes based on the Xiangya cohort and additional external BLCA cohorts using a random forest algorithm. A correlation was then done between the VM_Score and classical molecular subtypes, clinical outcomes, immunophenotypes, and treatment options for BLCA. With the VM_Score, it is possible to predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic potential of BLCA with high accuracy. The VM_Scores of high levels indicate a more anticancer immune response but a worse prognosis due to a more basal and inflammatory phenotype. The VM_Score was also found associated with low sensitivity to antiangiogenic and targeted therapies targeting the FGFR3, β-catenin, and PPAR-γ pathways but with high sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy. A number of aspects of BLCA biology were reflected in the VM_Score, providing new insights into precision medicine. Additionally, the VM_Score may be used as an indicator of pan-cancer immunotherapy response and prognosis.

Therapeutic potential of vasculogenic mimicry in urological tumors

“…Siglec15, a member of the sialic acid-bound immunoglobulin-like lectin family, is an emerging broad-spectrum target for normalizing cancer immunotherapy (113). Jiao et al found that BCa patients in the high Siglec15 group were more sensitive to targeting vascular mimicry-related signaling pathways (b-catenin, PPAR-g, and FGFR3 pathways) (114,115). Therefore, Siglec15 may be used as an indicator of targeted therapy for VM.…”

“…In BCa, DNA methylation plays a key role in early diagnosis, predicting prognosis, predicting therapeutic opportunities, and serving as a potential therapeutic target (116), 5-Methylcytosine (5mC) in DNA is the most important epigenetic modification that shapes TME by influencing genomic stability, determining cancer cell differentiation status, and selecting cell identity (117,118). Jiao et al found that the high 5 mC score group may not be sensitive to neoadjuvant chemotherapy, but there are several immunosuppressive oncogenic pathways significantly enriched in the heterogeneous high 5 mC score group associated with VM, including WNT-b-catenin network, FGFR3 network, and VEGFA (114,(119)(120)(121). These VM pathways may provide promising therapeutic opportunities for BLCA patients in the high 5mC scoring group.…”

“…Jiao et al. found that BCa patients in the high Siglec15 group were more sensitive to targeting vascular mimicry-related signaling pathways (β-catenin, PPAR-γ, and FGFR3 pathways) ( 114 , 115 ). Therefore, Siglec15 may be used as an indicator of targeted therapy for VM.…”

“…Jiao et al. found that the high 5 mC score group may not be sensitive to neoadjuvant chemotherapy, but there are several immunosuppressive oncogenic pathways significantly enriched in the heterogeneous high 5 mC score group associated with VM, including WNT-β-catenin network, FGFR3 network, and VEGFA ( 114 , 119 – 121 ). These VM pathways may provide promising therapeutic opportunities for BLCA patients in the high 5mC scoring group.…”

Preliminary findings on the development of a predictive model for BLCA based on disulfidptosis-associated IncRNAs signature

“…The highest incidence of bladder cancer currently falls in most developed regions of the world, with approximately 550,000 new cases each year [ 4 ]. BLCA is a heterogeneous disease, comprising several tumor subtypes with differences in histology, genomic aberrations, and prognosis [ 5 ]. The mode of cell death has an important role in the development of BLCA [ 6 ].…”