Biology subjects

Lueong, S. S.

Publications and source records attributed to Lueong, S. S..

4 recordsLinked to original sources

bioRxiv2025

Redirecting resistance evolution in BRAFV600 melanoma by inhibition of the peroxiredoxin-thioredoxin system

Drug-tolerant persister cells (DTPs) exhibit remarkable cell state heterogeneity and phenotypic evolvability. However, the central question of how DTPs epigenetically coordinate their metabolic flexibility to adapt early to therapeutic stress remains unanswered. We have recently shown that the histone demethylase KDM5B, which is intrinsically expressed in differentiated melanoma DTPs, reprograms the metabolic cell landscape. However, the exact mechanism by which KDM5B affects underlying metabolic enzymes, and whether this reveals new druggable vulnerabilities, remain unknown. By transcriptional and epigenetic profiling of BRAFV600 melanoma cells following KDM5B gene silencing, we discovered a direct molecular axis between the epigenetic regulator KDM5B and the PRDX/TXN ROS detoxification system. This metabolic axis is regulated independently of KDM5Bs demethylase activity. Furthermore, RNAi approaches and the pharmacological inhibition of the PRDX/TXN system led to ROS-induced cell death in differentiated melanoma DTPs and a delay of resistance development to MAPK inhibition. This process was independent of lipid-ROS-driven ferroptosis. Additionally, single-cell transcriptome analyses from pre-clinical melanoma models under continuous MAPK inhibitory treatment demonstrated altered cellular differentiation dynamics, with a reduction in the early evolution into the mesenchymal DTP state under concomitant PRDX inhibition. Interestingly, the degree of melanoma cell state differentiation at the onset of treatment was a major determinant for the transition towards the neural crest-like DTP state. Our study identified a high degree of epigenetic-metabolic connectivity and flexibility within the melanoma DTP pool and urges caution with single redox pathway-targeted strategies for tumor elimination in the future. Prospectively, our results point towards a new resistance targeting strategy for BRAFV600 melanoma patients based on pharmacological re-direction of the evolution of melanoma cell states already at therapy onset. HighlightsO_LITranscriptional and epigenetic profiling identified KDM5B as a regulator of the PRDX/TXN-ROS detoxification system C_LIO_LIPRDX inhibition increases the vulnerability of KDM5Bhigh DTPs to ROS, independent of ferroptosis C_LIO_LIPRDX inhibition delays resistance to MAPK inhibition in BRAFV600 melanoma cells C_LIO_LILongitudinal single-cell transcriptome analysis reveals that PRDX inhibition re-directs early DTP evolution C_LIO_LIPRDX/TXN gene expression is predictive for melanoma patient survival C_LI

cancer biology↗

bioRxiv2024

Key Regulatory Elements of the TGFbeta-LRRC15 Axis Predict Disease Progression and Immunotherapy Resistance Across Cancer Types

Transforming growth factor-beta (TGF{beta}) has dual roles in cancer, initially suppressing tumors but later promoting metastasis and immune evasion. Efforts to inhibit TGF{beta} have been largely unsuccessful due to significant toxicity and indiscriminate immunosuppression. Leucine-rich repeat-containing protein 15 (LRRC15) is a TGF{beta}-regulated antigen expressed by mesenchymal-derived cancer cells and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGF{beta}-driven LRRC15+ CAFs increased tumor infiltration of CD8+ T cells. However, the underlying pathobiological mechanisms prompting TGF{beta}s upregulation of LRRC15 expression are unclear. Using an integrated approach combining functional compound screening with single-cell RNA sequencing, we reveal key genomic features regulating TGF{beta}s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes--MMP2, SPARC, TGF{beta}R2, and WNT5B--central to TGF{beta}-induced LRRC15 pathobiology. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing co-treatment options.

pharmacology and toxicology↗

bioRxiv2022

SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis

BackgroundInflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and subsequent consequences on disease aggressiveness is less understood. MethodsMulti-omic analyses of 27 (~ 5000 samples) entities from the TCGA, GEO and in-house data was performed to investigate the molecular determinant of tumor aggressiveness. Using molecular loss of function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness was addressed. ResultsThe data revealed a significant association between somatic copy number alterations (sCNA) and tumor aggressiveness, with amplification of the transcription factor SOX2 being the most important feature among novel and known aggressiveness-associated genes such as ZIC5 and MYEOV. Mechanistically, SOX2 regulates a group of aggressiveness-related genes including the AP1 transcription factor FOSL2 to sustain pro-inflammatory pathway such as IL6-JAK-STAT3, TNFA and IL17 signaling pathways. Prolonged inflammation induces immunosuppression and further leads to activation of cytidine deamination and consequential DNA damage evidenced by enrichment in cytidine deamination mutational signatures in aggressive tumors. The resulting DNA damage affects tumor suppressor genes such as TP53, which was the most mutated gene in aggressive tumors compared with less aggressive tumors (38% vs 14%), thereby releasing cell cycle control. This was exemplified in Glioblastoma multiform, where TP53 and IDH1 mutations are predominant. IDH1 mutations were almost only seen in younger patients (>45 years, > 90%) and may explain the previously reported favorable prognosis. ConclusionTaken together, our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

cancer biology↗

bioRxiv2021

Functional metabolic phenotyping of human pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) lacks targeted treatment options. Although subtypes with transcriptome-based distinct lineage and differentiation features have been identified, deduced clinically actionable targets remain elusive. We here investigate functional metabolic features of the classical and QM (quasi-mesenchymal)/basal-like PDAC subtypes potentially exploitable for non-invasive subtype differentiation and therapeutic intervention. A collection of human PDAC cell lines, primary patient derived cells (PDC), patient derived xenografts (PDX) and patient PDAC samples were transcriptionally stratified into the classical and QM subtype. Functional metabolic analyses including targeted and non-targeted metabolite profiling (matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)), seahorse metabolic flux assays and metabolic drug targeting were performed. Hyperpolarized 13C-magnetic resonance spectroscopy (HP-MRS) of PDAC xenografts was used for in vivo detection of intra-tumoral [1-13C]pyruvate and [1-13C]lactate metabolism. We identified glycolysis and lipid metabolism/fatty acid oxidation as transcriptionally preserved metabolic pathways in QM and classical PDAC subtype respectively. However, these metabolic cues were not unambiguously functionally linked to one subtype. Striking functional metabolic heterogeneity was observed especially in primary patient derived cells with only individual samples representing high dependence on glycolysis or mitochondrial oxidation. Of note, QM cells actively use the glycolytic product lactate as oxidative mitochondrial fuel. Using HP-MRS, we were able to non-invasively differentiate glycolytic tumor xenografts with high intratumoral [1-13C]pyruvate to [1-13C]lactate conversion in vivo. Although PDAC transcriptomes indicate molecular subtype-associated distinct metabolic pathways, we found substantial functional metabolic heterogeneity independent of the molecular subtype. Non-invasive identification of highly glycolytic tumors by [1-13C]pyruvate/lactate HP-MRS support individualized metabolic targeting approaches.

cancer biology↗