Biology subjects

Keskus, A. G.

Publications and source records attributed to Keskus, A. G..

4 recordsLinked to original sources

bioRxiv2026

APOBEC3-driven neoantigen-rich cancers co-opt 1q23.3 amplification for tumor-intrinsic immune cloaking

Hypermutational processes, including those driven by the APOBEC3 family of cytidine deaminases, generate abundant neoantigens yet give rise to tumors that evade immune recognition. Here, using multi-omics analyses followed by functional validation, we identified a tumor-intrinsic immune-cloaking mechanism in neoantigen-rich epithelial cancers, characterized by coordinated suppression of antigen presentation, immune-recruiting cytokines and immune-checkpoint programs. In bladder cancer, genome-wide copy-number analysis identified recurrent 1q23.3 amplification as a genomic feature of a neoantigen-high/CD8-low tumor state. Within this locus, NECTIN4 emerged as the dominant candidate effector, outperforming extrachromosomal DNA status as a predictor of immune-neoantigen discordance. Similar associations were observed across breast and lung cancers. Functional studies demonstrated that NECTIN4 was sufficient to establish a T-cell-poor tumor microenvironment and confer resistance to PD-1 blockade in immunocompetent mice. Mechanistically, NECTIN4 engaged a DDR1-SHP2 axis that suppressed STAT1 phosphorylation, silencing tumor-cell immune-engagement programs. NECTIN4 blockade restored STAT1 activity and reduced tumor growth, indicating that the cloaked state is pharmacologically reversible. Mutational signature, breakpoint motif, timing and clonality analyses, together with APOBEC3B expression and germline genetic evidence, linked APOBEC3-mediated mutagenesis to recurrent 1q23.3 amplification encompassing NECTIN4. These findings reveal how neoantigen-generating mutational processes can be coupled to structural genome evolution to enable tumor-intrinsic immune cloaking through a therapeutically targetable NECTIN4-DDR1-SHP2 axis.

cancer biology↗

bioRxiv2026

A complete human pancreatic cancer genome

Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine.1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions.1-3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres.4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

genomics↗

bioRxiv2025

TP53-META, a meta-analysis tool for comparative transcriptomics of TP53 dependency: Examples from target silencing and liver fibrosis

BackgroundTP53 is the most frequently mutated transcription factor (TF) in sporadic cancers; and its targets exhibit dysregulation at the level of expression in both cancer and non-cancer pathologies. However, there is not yet a web-based tool that enables meta-analysis and visualization of TP53-related gene expression datasets, although several databases exist to access and annotate TP53 target information. To address this gap, we developed TP53-META, an interactive R Shiny-based web tool that allows users to upload and simultaneously analyze users or integrated public RNA-seq datasets for effects of TP53 depletion and/or induction on the transcriptome. ResultsTP53-META can be used to visualize significant expression clusters as well as TF-TF, pathway-pathway, disease-gene and treatment-gene networks to determine TP53 dependency of selected treatment contrasts. We demonstrated the utility of TP53-META through two case studies. In the first, using an in-house RNA-seq data from MCF7 cells treated with siRNAs against CHRNA5 and TP53, we identified TP53-independent and dependent transcriptomic changes by CHRNA5 depletion by comparing with selected public datasets in TP53-META. In the second, we demonstrated the user data upload functionality of TP53-META before meta-analysis and extracted commonly modulated TP53-related genes in liver fibrosis using public RNA-seq datasets. TP53-META is available at http://konulabapps.bilkent.edu.tr:3838/TP53-Meta1.5/ ConclusionsBy facilitating meta-analysis, clustering, and network-based visualizations, TP53-META enables researchers to efficiently integrate and explore TP53-related transcriptomic datasets from diverse sources, and help uncover robust expression patterns, and investigate context-specific TP53 functions.

bioinformatics↗

bioRxiv2020

ace2 expression is higher in intestines and liver while being tightly regulated in development and disease in zebrafish

Human Angiotensin I Converting Enzyme 2 (ACE2) that acts as a receptor for SARS-CoV-2 entry is highly expressed in human type II pneumocytes and enterocytes and similarly in other mammals and zebrafish (Danio rerio). The zebrafish genome has a highly conserved, one-to-one ortholog of ACE2, i.e., ace2, whose expression profile however has not yet been studied during development or in pathologies relevant to COVID-19. Herein, we identified significant development-, tissue- and gender-specific modulations in ace2 expression based on meta-analysis of zebrafish Affymetrix transcriptomics datasets (ndatasets=107, GPL1319 in GEO database). Co-expression network analysis of ace2 revealed distinct positively correlated (carboxypeptidase activity and fibrin clot formation), and negatively correlated (cilia biogenesis/transport and chromatin modifications) STRING network modules. Using additional transcriptomics datasets, we showed zebrafish embryos before 3 days post fertilization (dpf) exhibited low levels of ace2 that increased significantly until 4 dpf implicating a role for ace2 in organogenesis. Re-analysis of RNA-seq datasets from zebrafish adult tissues demonstrated ace2 was expressed highly in intestines, variably in liver, and at lower levels in other organs. In addition, zebrafish females and males showed significant dimorphism in their age-dependent expression of ace2, and between ovary and testis where the latter had higher levels. Moreover, we demonstrated ace2 expression was significantly modulated under different physiological and pathological conditions associated with development, diet, infection, and inflammation. Our findings implicate a novel translational role for zebrafish ace2 in differentiation and pathologies predominantly found in intestines and liver, in which the effects of SARS-CoV-2 could be detrimental.

molecular biology↗