Biology subjects

Verset, L.

Publications and source records attributed to Verset, L..

4 recordsLinked to original sources

bioRxiv2025

Prediction of Gemcitabine sensitivity in resectable Pancreatic Cancer using a Glycation Stress Transcriptomic Signature

BACKGROUND & AIMSPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited response to systemic therapy. Gemcitabine (GEM) benefits only a subset of patients. Methylglyoxal (MG), a glycolysis byproduct, has been linked to tumor behavior and therapy response in PDAC, suggesting potential as a stratification marker. METHODSWe developed a metabolically informed gene signature (MG-GEM) integrating MG- related glycolytic stress with clinical outcomes. Using the Puleo cohort (n=309), differential expression analysis between tumors with high and low MG stress identified 365 genes. LASSO Cox regression selected 16 prognostic genes, combined into a weighted risk score for patient stratification. MG GEM was validated in internal and external cohorts, including PRODIGE 24/CCTG PA6. Molecular, transcriptomic, and immune features were compared between high and low MG GEM groups. Finally, predictive performance was evaluated against the GemPred signature. RESULTSMG GEM divided PDAC patients into distinct risk groups with marked differences in overall and disease-free survival among GEM treated patients (OS 11.7 vs 27.2 months; DFS 7.6 vs 17.8 months, both p<0.0001). High MG-GEM tumors showed enrichment for KRAS G12D and SMAD4 mutations, basal and activated stroma subtypes, glycolytic metabolism, and reduced immune infiltration. Low MG-GEM tumors showed KRAS G12V, classical and immune subtypes, cholesterogenic metabolism, and adaptive immune favourable signatures. MG-GEM independently predicted GEM-specific clinical outcomes, irrespective of GemPred signature, and significantly enhanced patient stratification when combined with it. Within the PRODIGE-24/TGCC PA6 cohort, MG-GEM exhibited prognostic relevance and selectively identified patients who derived a survival benefit from adjuvant GEM, but not from FOLFIRINOX. CONCLUSIONSThe 16 gene MG GEM signature predicts prognosis in resected PDAC, reflects glycolytic stress driven chemoresistance, surpassing conventional molecular classifications. As a metabolically informed signature, MG-GEM holds promise for guiding chemotherapy selection and informing KRAS-targeted combination strategies, meriting further prospective clinical validation.

cancer biology↗

bioRxiv2025

Sox9-dependent plasticity of esophageal progenitors is fine-tuned by cues from the microenvironment

Cell plasticity governs tissue regeneration but can also drive metaplasia, the replacement of one cell type with another. This process increases the risk of cancer development in several tissues, including esophagus. Esophageal metaplasia development partly depends on keratinocyte plasticity, making regulation of esophageal progenitor fate critical. We previously identified Sox9 as instrumental in regulating esophageal cell plasticity following Hedgehog pathway activation. Our current study reveals that Hedgehog indirectly regulates Sox9 by modifying epithelial-stromal communication. This activates TGF-{beta} and BMP pathways in epithelial cells, which synergistically regulate Sox9 and stimulate a transcriptomic program resembling squamo-columnar junction progenitors, which are prone to initiate metaplasia. Importantly, we demonstrate pharmacological modulation of this plasticity in vivo. Indeed, Ibuprofen inhibits Hedgehog-induced Sox9 expression by directly targeting epithelial cells, providing proof of concept for pharmacological intervention in cell plasticity with implications for regenerative medicine and metaplasia treatment.

cell biology↗

bioRxiv2024

Duodenal organoids from metabolic dysfunction-associated steatohepatitis patients exhibit altered digestive homeostasis

Background and AimsMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Recent research underscores the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. Here, we investigated whether the duodenal epithelium of MASH patients, could exhibit intrinsic dysfunctions. MethodsDuodenal epithelial organoids were generated from 16 MASH patients and 14 healthy controls. Biopsies and patient-derived organoid transcriptomes were then analyzed to evaluate if specific intestinal pathways were differentially modulated in MASH subjects. Functional assays were performed to assess the duodenal epithelial digestive potential and barrier functionality. ResultsOrganoid formation efficiency was similar between control-derived epithelial organoids (CDEOs) and MASH-derived epithelial organoids (MDEOs) (71% and 69%, respectively). Despite global heterogeneity in growth patterns, MDEOs frequently exhibited cystic spheroid morphology. MDEOs displayed altered digestive homeostasis associated with reduced mature absorptive cell fate, but they retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Additionally, MDEOs misexpressed components of tight and adherens junctions and desmosomes compared to controls. However, MDEOs maintained pore and leak pathway integrity, indicating that the duodenal epithelial barrier remained functionally preserved under tested conditions. ConclusionsThis study provides evidence that the duodenal epithelium of MASH patients exhibits significant alterations in its digestive and barrier functions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal homeostasis.

cell biology↗

bioRxiv2024

Favorable histo-molecular remodeling of pancreatic ductal adenocarcinoma after Total Neoadjuvant Therapy including Stereotactic Body Radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest tumors with slow progress in systemic therapies due to its peculiar and resistant tumor microenvironment. Inclusion of isotoxic high-dose stereotactic body radiation therapy (iHD-SBRT) into a total neoadjuvant strategy (TNT) is promising for the treatment of localized PDAC. However, the histo-molecular effects of iHD-SBRT are still poorly explored. In this study, we have shown that TNT, associating FOLFIRINOX [FFX] followed by iHD-SBRT, leads to significant and long-lasting remodeling of PDAC, affecting its stromal, metabolic, and molecular features. Contrary to FFX alone, TNT is able to enrich tumors with Classical and Inactive stromal signatures associated with better prognosis. Furthermore, iHD-SBRT seems capable to counteract several of the detrimental modulatory effects induced by FFX such as Epithelial-to-Mesenchymal Transition or angiogenesis. Additionally, we identified inflammatory cancer-associated fibroblasts signatures as an important prognostic factor. This work provides new rationale to sequentially combine FFX with iHD-SBRT and suggests new pathways that can be targeted in combination with a TNT. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/591890v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@155da78org.highwire.dtl.DTLVardef@17a1ab7org.highwire.dtl.DTLVardef@16fe522org.highwire.dtl.DTLVardef@12c5870_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗