Biology subjects

Lombard, D.

Publications and source records attributed to Lombard, D..

4 recordsLinked to original sources

bioRxiv2026

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8 T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8 T cells via lipid peroxidation. FADS2 inhibition restores CD8 T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinsons disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8 T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.

Cancer Biology↗

bioRxiv2026

Matrix nucleotide homeostasis couples energetic state to mitochondrial translation

Mitochondrial protein synthesis is essential for oxidative phosphorylation, yet how organellar energetic state regulates the mitochondrial translation machinery remains poorly understood. Here, we show that mitochondrial translation is acutely sensitive to ATP synthase-dependent bioenergetic state. Pharmacological inhibition of the F1Fo-ATP synthase with oligomycin or citreoviridin rapidly and selectively suppresses mitochondrial protein synthesis, while mitoribosome profiling reveals a genome-wide loss of productive ribosome engagement. ATP synthase inhibition induces inner-membrane hyperpolarization, depletes bioavailable matrix ATP, and reduces matrix GTP availability. Relieving hyperpolarization restores nucleotide pools and mitochondrial translation despite persistent ATP synthase inhibition, whereas selective restoration of matrix GTP markedly rescues protein synthesis when adenine nucleotide exchange is restricted. These findings identify matrix GTP availability as a proximal energetic constraint on mitochondrial translation and reveal an organelle-intrinsic mechanism coupling ATP synthase-dependent bioenergetic state to mitoribosome activity.

cell biology↗

bioRxiv2025

NAB2-STAT6 Fusion Proteins Drive Nuclear Condensate Formation and Transcriptional Reprogramming in Solitary Fibrous Tumors

Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2-STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4-STAT6ex2 fusion variant forms nuclear condensates via liquid-liquid phase separation (LLPS) in engineered fibroblast models and primary SFT cells. These condensates co-localize with BRD4S and EGR1, key transcriptional regulators, and are functionally active, driving widespread transcriptional reprogramming. Treatment with Mithramycin A, a compound that disrupts EGR1-DNA interactions, dissolves NAB2-STAT6 condensates and reverses their aberrant gene expression and chromatin binding signatures. Our findings uncover a previously unrecognized role for NAB2-STAT6 in condensate-mediated oncogenic signaling and provide a mechanistic rationale for condensate-targeted therapy in SFT.

cancer biology↗

bioRxiv2024

Targeting Endoplasmic Reticulum Stress and Nitroso-Redox Imbalance in Neuroendocrine Prostate Cancer: The Therapeutic Role of Nitric Oxide

Neuroendocrine prostate cancer (NEPC) is an aggressive and therapy-resistant subtype of prostate cancer. Current standard-of-care treatment for NEPC involves chemotherapies, which largely exert their cytotoxic effects by forming DNA crosslinks, disrupting DNA replication and transcription in NEPC cells. However, these therapies are often met with resistance, partly due to increased endoplasmic reticulum (ER) stress, which facilitates cancer cell survival and adaptive mechanisms. Despite its critical role, the molecular landscape underlying ER stress in NEPC remains inadequately understood. Here we showed that ER stress is intimately linked to the metabolic reprogramming of NEPC cells, a process that supports their transition from adenocarcinoma to a neuroendocrine phenotype. We identified MYCN as a key driver of this process, promoting unfolded protein response (UPR) elements that enhance ER stress by increasing the efflux of calcium ions through the ER which later is absorbed by the mitochondria and assist in increasing the overall glycolytic stress, thereby adding to the extended survival and metastatic potential of an NEPC cell. Our previous studies highlighted the importance of S-nitrosylation as a protein modification that is dysregulated in high-grade PCa. In this context, structural analysis of MYCN revealed potential S-nitrosylation sites at the positions Cys4, 186, and 464, respectively. However, similar to the castration-resistant stage, this modification is hindered in NEPC due to impaired nitric oxide (NO) production from dysregulated endothelial nitric oxide synthases (eNOS). We found that exogenous NO supplementation S-nitrosylates MYCN, reducing its binding to protein molecules which are essential to assist with increasing ER stress in NEPC cells. Exogenous supplementation of NO reduced the overall tumor burden in the mice harboring orthotopic NEPC cells and reduced the metastasis to the brain and liver. In conclusion, the findings from this study enrich our understanding of the mechanisms driving the ER stress responses in NEPC phenotype and how NO supplementation could pave the way as potential therapeutics for this challenging cancer. HIGHLIGHTSO_LIEndoplasmic reticulum (ER) stress is intricately linked to metabolic reprogramming, which supports the transition from prostate adenocarcinoma to neuroendocrine prostate cancer (NEPC). C_LIO_LIMYCN increases the ER stress in NEPC cells and is correlated with increased nitroso-redox imbalance. C_LIO_LIStructural analysis reveals potential S-nitrosylation sites on MYCN. Exogenous nitric oxide (NO) supplementation induces S-nitrosylation, disrupting MYCNs role in enhancing ER stress. C_LIO_LINO supplementation reduced tumor burden and metastasis in NEPC-bearing mice, highlighting its potential as a therapeutic avenue for NEPC. C_LIO_LIExogenous NO supplementation inhibits ER stress by targeting unfolded protein response (UPR) elements and decreasing calcium ion efflux, inhibiting the glycolytic stress in NEPC. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/624202v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1fb292forg.highwire.dtl.DTLVardef@4d00f7org.highwire.dtl.DTLVardef@17a7f43org.highwire.dtl.DTLVardef@1393286_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗