Biology subjects

Papadopoli, D.

Publications and source records attributed to Papadopoli, D..

4 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

A Chemical-Genetic Interaction Matrix Reveals Drug Mechanism and Genetic Architecture

To probe drug mechanism of action (MOA) and interrogate the genetic architecture of human cells, we carried out isogenic genome-wide CRISPR/Cas9 knockout screens against 310 diverse drugs, bioactive compounds, and stress conditions. Stringent statistical correction for gene knockout fitness defects yielded a large-scale matrix of >12,000 high confidence chemical-genetic interactions (CGIs). This dataset revealed many previously unappreciated off-target effects for well-characterized compounds and novel MOAs for uncharacterized compounds. The CGI matrix uncovered dense genetic modules that yielded new biological insights into phospholipidosis, mitotic regulation, metabolism, the DNA damage response, and mTOR signaling. The dataset allowed identification of multi-drug sensitization and resistance mechanisms, inference of gene function, elaboration of cross-process connectivity, evaluation of the cell type specificity of CGIs, prediction of chemical synergism, and extensive annotation of understudied genes. This resource provides a map of the genetic landscape in human cells and a framework to help guide drug discovery.

systems 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↗