Biology subjects

Meeks, J. J.

Publications and source records attributed to Meeks, J. J..

3 recordsLinked to original sources

bioRxiv2024

Genomic and transcriptomic profiling of high-risk bladder cancer reveals diverse molecular and microenvironment ecosystems

Despite surgical resection, rigorous endoscopic surveillance, and immunotherapy with the Bacillus Calmette-Guerin (BCG) vaccine, 30% of high-risk bladder cancers recur, and 10% result in fatal outcomes within two years of diagnosis. The global shortage of BCG underscores the urgent need for alternative or complementary therapeutic strategies. To address this, we integrated transcriptomic profiling and targeted genomic sequencing to identify four consensus intrinsic subtypes of bladder cancer. Initially derived from bulk RNA profiling, these subtypes were further validated at the cellular and tissue-compartment levels using single-cell RNA sequencing and spatial transcriptomics. Notably, we identified a subtype of inflamed tumors with enhanced endogenous retroelement expression and increased commensal bacterial presence, which showed the highest responsiveness to BCG therapy. Additionally, we developed a machine learning-based model incorporating composite molecular features to predict recurrence risk, achieving a high accuracy (AUC = 0.90). Our findings establish a molecular precision framework for bladder cancer and nominate novel therapeutic targets to reduce reliance on BCG immunotherapy.

cancer biology↗

bioRxiv2019

Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

Locally advanced urothelial carcinoma has a poor survival despite a response to immunotherapy in approximately 25% of patients. To develop new therapies targeting other immune checkpoints, we identified increased expression of the T cell inhibitor protein, B7-H4 (VTCN1, B7S1, B7X), during tumor development of murine bladder cancer. Evaluation of B7-H4 in human bladder cancer by single-cell RNA-Seq and immune mass cytometry showed that B7-H4 is expressed by luminal tumors that are not normally responsive to PD-1 inhibitors. Additionally, overexpression B7-H4 was associated with significantly worse patient survival. In support of clinical translation, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-{gamma} secretion by CD4+ and CD8+ T cell. While the study of B7-H4 in mouse cancer models has been difficult using tumor cell lines, our findings show that B7-H4 expression increased at 3 months after exposure to BBN on CD11b+ monocytes/macrophages and delivery of anti-B7-H4 antibody resulted in decreased tumor size and increased CD8 immune cell infiltration with increased CD8+/IFN-{gamma}-producing T cells and a complimentary decrease in tumor infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage. This data suggests that novel anti-B7-H4 antibodies maybe a viable target for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

cancer biology↗

bioRxiv2017

APOBEC-Mediated Mutagenesis In Urothelial Carcinoma Is Associated With Improved Survival, Mutations In DNA Damage Response Genes, And Immune Response

BackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.\n\nMethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into \"APOBEC-high\" and \"APOBEC-low\" tumors based on APOBEC enrichment score. Analysis was performed with R.\n\nFindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.\n\nInterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate for APOBEC3A and APOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.\n\nHighlightsO_LIABPOEC enzymes, particularly APOBEC3A and APOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancer\nC_LIO_LITumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations in KRAS and FGFR3\nC_LIO_LIAPOBEC enrichment is associated with upregulation of genes involved in the immune response\nC_LI

cancer biology↗