Biology subjects

Avizonis, D.

Publications and source records attributed to Avizonis, D..

8 recordsLinked to original sources

bioRxiv2026

Lactate-fueled hydride transfer metabolon drives breast cancer metastasis

Metabolic plasticity of cancer cells plays a major role in metastasis. Use of alternative carbon fuels (e.g., lactate) boosts metabolic plasticity, but the underlying mechanisms remain obscure. We show that lactate dehydrogenase B (LDHB) cooperates with the hydride ion transfer complex (HTC) comprised of pyruvate carboxylase (PC), malic enzyme (ME1) and malate dehydrogenase (MDH1) to form a metabolon that confers metabolic flexibility through lactate assimilation under physiological conditions. HTC/LDHB metabolon assembles in the aggressive breast cancer subtypes and reprograms nicotinamide adenine dinucleotide (NAD) metabolism to promote migration, invasion and escape from anoikis - thereby driving metastasis. Altogether, this work identifies a lactate-fueled metabolon that propels metastatic dissemination of breast cancer.

Cancer Biology↗

bioRxiv2026

Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools

The anaphase promoting complex/cyclosome (APC/C) is a large, ubiquitin ligase and a central regulator of cell cycle progression. By targeting key substrates for degradation during mitosis and G1 phase, the APC/C coordinates metabolic fluctuations that occur during the cell cycle. A diverse range of viruses have convergently evolved mechanisms to bind and inhibit the APC/C; however, a molecular understanding for these interactions has never been demonstrated. Here, we use chicken anemia virus (CAV), a small single-stranded DNA virus encoding only three proteins, to demonstrate the importance of viral APC/C inhibition during replication. We show that the Vp3 protein of CAV inhibits the APC/C, causing a dramatic mitotic arrest during infection. Mutant virus lacking Vp3 are defective for replication and can be rescued by APC/C inhibition. Metabolomic profiling during CAV infection revealed that Vp3 expression mediates a broad increase in nucleotide pools. Moreover, viral inhibition of the APC/C resulted in stabilization of enzymes required for nucleotide biosynthesis. These findings suggest that the APC/C is a general target of many viruses to elevate nucleotide levels and facilitate viral genome replication. Author SummaryViruses dramatically reshape the cells they infect in order to replicate. To do this efficiently, many viruses disrupt the hosts normal control systems, particularly those that regulate cell growth and division. One such system is the anaphase promoting complex/cyclosome (APC/C), a key cellular machine that controls when specific proteins are broken down during the cell cycle. Surprisingly, a wide range of viruses--including adenovirus, HIV, human papillomavirus, herpesvirus, and others--have been shown to interfere with the APC/C. Until now, however, it was unclear why so many unrelated viruses target this same pathway. In our study, we used chicken anemia virus (CAV), one of the smallest known animal viruses, as a simple model to uncover the underlying mechanism. CAV produces just three proteins, one of which--called VP3--strongly inhibits the APC/C. We found that this inhibition increases the availability of nucleotides, the basic building blocks needed to copy viral DNA. By disrupting normal cell cycle control, the virus effectively redirects cellular resources toward its own replication. These findings reveal APC/C inhibition as a common and powerful strategy used by diverse viruses, offering new insight into how viruses exploit host cells and highlighting potential targets for future antiviral therapies.

microbiology↗

bioRxiv2025

EZH2 Inhibition Induces an Integrated Stress Response Driving Glutamine-Dependent Vulnerability in TNBC

EZH2, the catalytic subunit of Polycomb Repressive Complex II, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition induces significant changes in chromatin landscapes and gene expression, it has a limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrate that EZH2 inhibition leads to the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4 activation, EZH2 inhibition enhances amino acid flux and promotes glutaminolysis, in turn activating mTOR signaling to support TNBC cell survival. Pharmacological targeting of this metabolic adaptation with a glutaminase (GLS) inhibitor in combination with EZH2 inhibition significantly impairs TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.

cancer biology↗

bioRxiv2024

Reduction in ETFDH expression optimizes cancer cell bioenergetics

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM-6 cells, and its expression is reduced across human cancers. ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics and accelerates neoplastic growth by activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerate neoplastic growth.

cancer biology↗

bioRxiv2023

MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors

Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results showed that mTORC1 activation caused by abrogation of TSC2 increased H3K27me3 but not H3K4me3 or H3K9me3. This appeared to be mediated via the induction of EZH2 protein synthesis, downstream of 4EBPs. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects. HighlightsO_LIParadoxically, both mTOR activation and inhibition induce H3K27me3. C_LIO_LIThe effect of mTOR inhibitors on H3K27me3 are not secondary to cell cycle arrest. C_LIO_LIH3K27me3 triggered by mTOR suppression coincides with perturbations in EZH1/2 ratio. C_LIO_LIH3K27me3 impacts on the anti-proliferative effects of mTOR inhibitors. C_LI

molecular biology↗

bioRxiv2021

Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN. HIGHLIGHTSO_LIPaclitaxel induces intra-axonal calcium flux C_LIO_LISarm1-dependent cADPR production promotes axonal calcium elevation and degeneration C_LIO_LIAntagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo C_LI

neuroscience↗

bioRxiv2019

Repression of LKB1 by miR-17~92 sensitizes MYC-dependent lymphoma to biguanide treatment

Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA cluster miR-17[~]92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate that Myc+ lymphoma cells with elevated miR-17[~]92 expression display increased sensitivity to biguanide treatment both in cell viability assays in vitro and tumor growth assays in vivo. This increased biguanide sensitivity is driven by miR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration in miR-17[~]92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17[~]92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17[~]92 expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors. One Sentence SummarymiR-17[~]92 expression in Myc+ tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.

cancer biology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗