Biology subjects

Laurent, D.

Publications and source records attributed to Laurent, D..

3 recordsLinked to original sources

bioRxiv2026

Graph-based Drug Decomposition for Anticancer Response Modeling

This paper studies the molecular effects on ex vivo drug response in pediatric acute myeloid leukemia (AML). We firstly estimate dose-response relationships through linear and mixed-effects models, capturing both patient-specific heterogeneity and drug-level effects. Then, drug identifiers are decomposed into curated molecular descriptors and their higher-order interactions, yielding a structured, interpretable representation of chemical properties. To handle the resulting high-dimensional system, we introduce a specialized graph-based drug decomposition and selection, enabling a computationally tractable estimation of the molecular effects on ex vivo drug response. This strategy uncovers the molecular features most strongly associated with cellular viability, providing a biologically grounded and transparent alternative to black-box predictive methods. By directly linking molecular structure to therapeutic outcomes, our framework supports a novel mathematical-programming-based drug-combination selection and cost-efficient compound prioritization in pre-clinical leukemia research.

bioinformatics↗

bioRxiv2021

In vivo CRISPRi screen reveals the differential requirement for mitochondrial respiratory chain function between in vivo and in vitro tumor growth

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and significant processes such as tumor dissemination and metastases remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells downregulate glycolytic mechanisms. These studies demonstrate that discrete perturbations of mitochondrial metabolism impact in vivo tumor growth in a context-specific manner and provides systems-level evidence that respiratory function modulates tumor growth in vivo, suggesting that ATP limits growth and metastatic potential.

cancer biology↗

bioRxiv2019

Absolute measurement of the tissue origins of cell-free DNA in the healthy state and following paracetamol overdose

BackgroundDespite the emergence of cell-free DNA (cfDNA) as a clinical biomarker in cancer, the tissue origins of cfDNA in healthy individuals have to date been inferred only by indirect and relative measurement methods, such as tissue-specific methylation and nucleosomal profiling.\n\nMethodsWe performed the first direct, absolute measurement of the tissue origins of cfDNA, using tissue-specific knockout mouse strains, in both healthy mice and following paracetamol (APAP) overdose. We then investigated the utility of total cfDNA and the percentage of liver-specific cfDNA as clinical biomarkers in patients presenting with APAP overdose.\n\nResultsAnalysis of cfDNA from healthy tissue-specific knockout mice showed that cfDNA originates predominantly from white and red blood cell lineages, with minor contribution from hepatocytes, and no detectable contribution from skeletal and cardiac muscle. Following APAP overdose in mice, total plasma cfDNA and the percentage fraction originating from hepatocytes increased by ~100 and ~19-fold respectively. Total cfDNA increased by an average of more than 236-fold in clinical samples from APAP overdose patients with biochemical evidence of liver injury, and 18-fold in patients without biochemically apparent liver injury. Measurement of liver-specific cfDNA, using droplet digital PCR and methylation analysis, revealed that the contribution of liver to cfDNA was increased by an average of 175-fold in APAP overdose patients with biochemically apparent liver injury compared to healthy subjects, but was not increased in overdose patients with normal liver function tests.\n\nConclusionsWe present a novel method for measurement of the tissue origins of cfDNA in healthy and disease states and demonstrate the potential of cfDNA as a clinical biomarker in APAP overdose.

pharmacology and toxicology↗