Biology subjects

Akdemir, K. C.

Publications and source records attributed to Akdemir, K. C..

6 recordsLinked to original sources

bioRxiv2025

Oncogenic drivers shape the tumor microenvironment in human gliomas

Gliomas are aggressive and heterogeneous brain tumors with limited treatment options. While oncogenic mutations in gliomas have been well-characterized, their impact on the tumor microenvironment remains poorly understood. To investigate how genomic alterations may influence the glioma microenvironment, we performed an integrative multiomic and spatial transcriptomic analysis of 93 glioma samples (46 IDH-mutant gliomas and 47 IDH-wildtype glioblastoma) from 69 patients representing both primary and recurrent stages. Using whole-genome sequencing, chromatin conformation capture (Hi-C), RNA-seq, and single-cell spatial transcriptomics (Xenium), we defined how major driver mutations influence spatial tumor organization. We found that IDH-mutant gliomas frequently harbored inflammatory microglia expressing CX3CR1 specifically within their astrocyte-like malignant neighborhoods. In contrast, glioblastomas demonstrated relatively higher T-cell infiltration and enrichment of immunosuppressive myeloid cell populations. We further compared glioblastomas harboring EGFR amplifications due to extrachromosomal DNA (ecDNA) amplifications versus linear chromosomal 7 gains. Tumors with EGFR ecDNA displayed increased presence of mesenchymal-like malignant cells, and higher interactions between pericytes and mesenchymal-like malignant cells, likely driven by hypoxia-associated vascular proliferation. Our findings reveal that the mode of oncogene amplification--linear versus ecDNA--shapes distinct tumor architectures and transcriptional dynamics. Taken together, our study highlights the role of oncogenic drivers in shaping the glioma microenvironment, revealing subtype-specific cellular ecosystems that could inform targeted therapeutic strategies.

genomics↗

bioRxiv2025

Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS-chemokine-myeloid axis

Chromosomal instability (CIN), a characteristic feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and therapy resistance, presenting an intractable problem in cancer treatment. CIN leads to constitutive stimulation of the innate immune cGAS-STING pathway, which has been typically linked to anti-tumor immunity. However, despite the high CIN burden in EAC, the cGAS- STING pathway remains largely intact. To address this paradox, we developed novel esophageal cancer models, including a CIN-isogenic model, discovering myeloid-attracting chemokines - with the chemokine CXCL8 (IL-8) as a prominent hit - as conserved CIN-driven targets in EAC. Using high-resolution multiplexed immunofluorescence microscopy, we quantified the extent of ongoing cGAS-activating CIN in human EAC tumors by measuring cGAS-positive micronuclei in tumor cells, validated by orthogonal whole-genome sequencing-based CIN metrics. By coupling in situ CIN assessment with single-nucleus RNA sequencing and multiplex immunophenotypic profiling, we found tumor cell-intrinsic innate immune activation and intratumoral myeloid cell inflammation as phenotypic consequences of CIN in EAC. Additionally, we identified increased tumor cell-intrinsic CXCL8 expression in CINhigh EAC, accounting for the inflammatory tumor microenvironment. Using a novel signature of CIN, termed CINMN, which captures ongoing CIN-associated gene expression, we confirm poor patient outcomes in CINhigh tumors with signs of aberrantly rewired cGAS-STING pathway signaling. Together, our findings help explain the counterintuitive maintenance and expression of cGAS-STING pathway components in aggressive, CINhigh tumors and emphasize the need to understand the contribution of CIN to the shaping of a pro-tumor immune landscape. Therapeutic strategies aimed at disrupting the cGAS-driven inflammation axis may be instrumental in improving patient outcomes in this aggressive cancer.

cancer biology↗

bioRxiv2024

In Situ Single-Cell Spatial Profiling of Matrisome Gene Expression in Glioblastoma

The human brain contains a rich milieu of extracellular matrix (ECM) components that are often dysregulated in pathologies including the malignant cancer glioblastoma (GBM). Here, we have used in situ single-cell spatial transcriptomic platforms to map the expression patterns of nearly 400 ECM genes in normal brain and GBM samples. Our analysis identifies at least four different GBM cell populations with unique ECM expression profiles that show spatial enrichment in distinct intratumor regions. Spatial mapping also demonstrates largely non-overlapping expression signatures of various ECM components in GBM stromal cell types, particularly in vascular endothelial cells and reactive microglia/macrophages. Comparisons of GBM (IDH1 wild type) versus lower-grade II and III astrocytoma samples (IDH1 R132H) identifies differential expression of key ECM components, including elevated levels of select ECM glycoproteins (IGFBP2 and MGP) and ECM-affiliated proteins (ANXA1 and ANXA2). In addition, we detect spatially enriched expression of COL8A1 (collagen), LUM (proteoglycan), and POSTN (ECM glycoprotein) in perivascular stromal cells in GBM but not in lower grade tumors. Computational analysis of putative ligand-receptor interactions reveals novel ECM communication networks between cancer cells and stromal components, particularly in regions of GBM microvascular proliferation and pseudopalisading necrosis. In summary, this comprehensive spatial map provides new insights into microenvironmental control of GBM initiation and progression and identifies potential therapeutic targets in the ECM.

cancer biology↗

bioRxiv2021

Pan-cancer landscape of AID-related mutations, composite mutations and its potential role in the ICI response

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity. In BriefA combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors. Highlights* Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data * Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers * AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection * AID mutational load predicts response and is associated with favorable outcome in ICI treated patients

bioinformatics↗

bioRxiv2018

Process-specific somatic mutation distributions vary with three-dimensional genome structure

Somatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Bockler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

genomics↗

bioRxiv2017

Spatial Genome Organization as a Framework for Somatic Alterations in Human Cancer

Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Microscopic studies concluded that genome organization inside the nucleus is not random and chromosomes within the nucleus create territories1. More recent chromosome conformation studies have revealed that mammalian chromosomes are structured into tissue-invariant topologically associating domains (TADs) where the DNA within a given domain interacts more frequently together than with regions in other domains2,3. Genes within the same TADs represent similar expression and histone-modification profiles4. In addition, enhancer-promoter pairs within the same TAD respond similarly to hormone induction5 or differentiation cues6. Therefore, regions separating different TADs (boundaries) have important roles in reinforcing the stability of these domain-wide features. Indeed, TAD boundary disruptions in human genetic disorders7,8 or human cancers lead to misregulation of certain genes9,10, due to de novo enhancer exposure to promoters. Here, to understand effects and distributions of somatic structural variations across TADs, we utilized single nucleotide variations, deletions, inversions, tandem-duplications and complex rearrangements from 2658 high-coverage whole genome sequencing data across various cancer types with paired normal samples. We comprehensively profiled structural variations with respect to their effect on TAD boundaries, on the regulation of genes in human cancers.

genomics↗