Biology subjects

Thongon, N.

Publications and source records attributed to Thongon, N..

4 recordsLinked to original sources

bioRxiv2025

NNMT is a biomarker of prostate cancer cells with a mesenchymal phenotype and induces sensitivity to metabolic agents

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is essential for identifying patient subgroups most likely to benefit from NAMPT-targeted therapies. Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is defined by androgen receptor (AR) independence, YAP/TAZ dependency, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key mediator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells. Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues mesenchymal CRPC cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) loss. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC- SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes, as well as in murine prostate cancer cells with mesenchymal/stemness phenotypes. In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/651153v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@de4237org.highwire.dtl.DTLVardef@1cd577corg.highwire.dtl.DTLVardef@2aa97corg.highwire.dtl.DTLVardef@dd2ac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

IL-1B-mediated inflammatory signaling drives ineffective erythropoiesis in early-stage myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of incurable hematopoietic stem cell (HSC) neoplasms characterized by peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia. MDS represent the final stage in a continuum of HSCs genetic and functional alterations and are preceded by a premalignant phase, clonal cytopenia of undetermined significance (CCUS). Dissecting the mechanisms of CCUS maintenance may uncover therapeutic targets to delay or prevent malignant transformation. Here, we demonstrate that DNMT3A and TET2 mutations, the most frequent mutations in CCUS, induce aberrant HSCs differentiation towards the myeloid lineage at the expense of erythropoiesis by upregulating IL-1{beta}-mediated inflammatory signaling and that canakinumab rescues red blood cell transfusion dependence in early-stage MDS patients with driver mutations in DNMT3A and TET2. This study illuminates the biological landscape of CCUS and offers an unprecedented opportunity for MDS intervention during its initial phase, when expected survival is prolonged.

cancer biology↗

bioRxiv2023

Targeting MCL1-driven anti-apoptotic pathways to overcome hypomethylating agent resistance in RAS-mutated chronic myelomonocytic leukemia

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells functions. HSPCs expanded at disease progression and relied on the NF-KB pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway- mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway- mutated CMML.

cancer biology↗

bioRxiv2023

Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation. STATEMENT OF SIGNIFICANCEMetabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.

cancer biology↗