Biology subjects

Vogel, R. I.

Publications and source records attributed to Vogel, R. I..

4 recordsLinked to original sources

bioRxiv2025

Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis

Mutational processes are thought to act independently and additively. We challenge this view by demonstrating that DNA-adducting agents sensitize the genome to mutagenesis by APOBEC enzymes. A model tobacco carcinogen (NQO) triggers a 100-fold increase in APOBEC3B- catalyzed signature mutations and elevates oral carcinoma levels in vivo. A hallmark of this unidirectional synergy is strand-coordinated pairs of APOBEC signature mutations within 32nt of each other (didyma). Biochemical experiments show that APOBEC3B can catalyze didyma formation, and genetic studies demonstrate requirements for APOBEC3B and functional nucleotide excision repair (XPA in human cells and Rad14 in yeast). Analyses of lung and head & neck cancers show that APOBEC mutagenesis and didyma are elevated in tumors from smokers compared to non-smokers. Additional tumor types with links to DNA-adducting agents also exhibit didyma. These studies support a model in which DNA-adducting carcinogens activate nucleotide excision repair and amplify mutagenesis by APOBEC enzymes in cancer.

cancer biology↗

bioRxiv2023

Human APOBEC3B promotes tumor heterogeneity in vivo including signature mutations and metastases

The antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many different cancers. Despite over 10 years of work, a causal relationship has yet to be established between APOBEC3B and any stage of carcinogenesis. Here we report a murine model that expresses tumor-like levels of human APOBEC3B after Cre-mediated recombination. Animals appear to develop normally with full-body expression of APOBEC3B. However, adult males manifest infertility and older animals of both sexes show accelerated rates of tumorigenesis (mostly lymphomas or hepatocellular carcinomas). Interestingly, primary tumors also show overt heterogeneity, and a subset spreads to secondary sites. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Elevated levels of structural variation and insertion-deletion mutations also accumulate in these tumors. Together, these studies provide the first cause-and-effect demonstration that human APOBEC3B is an oncoprotein capable of causing a wide range of genetic changes and driving tumor formation in vivo.

cancer biology↗

bioRxiv2022

Treatment with Tumor-Treating Fields (TTFields) Suppresses Intercellular Tunneling Nanotube Formation In Vitro and Upregulates Immuno-Oncologic Biomarkers In Vivo in Malignant Mesothelioma

Intercellular communication is critical for the development of invasive cancers. Multiple forms of intercellular communication have been well characterized, involving diffusible soluble factors or contact-dependent channels for immediately adjacent cells. Over the past 1-2 decades, the emergence of a unique form of F-actin-based cellular protrusion known as tunneling nanotubes (TNTs) has filled the niche of long-range cell-contact dependent intercellular communication that facilitates cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. The cellular machinery of TNT-mediated transport is an area of active investigation, and microtubules have been implicated in this process as they are in other membranous protrusions. Tumor-Treating Fields (TTFields) therapy is a novel therapeutic strategy in clinical use for patients with advanced cancers, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. Other mechanisms of action have also been demonstrated. In this study, we investigated the effects of TTFields on TNTs in malignant pleural mesothelioma (MPM) in vitro and also on the spatial transcriptomic landscape in vivo. We found that applying TTFields at 1.0 V/cm significantly suppressed TNT formation in a biphasic MPM cell line (MSTO-211H), but not in sarcomatoid MPM (VAMT). At these parameters, TTFields significantly reduced cell count in MSTO-211H, but did not significantly alter intercellular transport of mitochondria via intact TNTs. To understand how TTFields may impact expression of genes with known involvement to TNT formation and overall tumor growth, we performed spatial genomic assessment of TTFields-treated tumors from an in vivo animal model of MPM, and detected upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. In this study, we report novel cellular and molecular effects of TTFields in relation to tumor communication networks enabled by TNTs and related molecular pathways. These results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies; and also identify the ability of TTFields to potentially remodel the tumor microenvironment, thus enhancing response to immunotherapeutic drugs.

cancer biology↗

bioRxiv2020

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-{kappa}B signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

cancer biology↗