Bellahcene, A. | bioRxiv Science

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↗

bioRxiv2021

Tumor-Antagonizing Fibroblasts Secrete Prolargin as Tumor Suppressor in Hepatocellular Carcinoma

Systemic treatment of hepatocellular carcinoma (HCC) targets the tumor microenvironment (TME) by combining immunotherapy with angiogenesis inhibitors. Cancer-associated fibroblasts (CAF) are important components of the TME, however their targeting in clinics remains challenging. To this end, the existence of tumor supressing CAF and their poor characterisation is a major conundrum. Starting from proteomics and single cell analysis, we outline CAF heterogeneity in HCC and describe a subtype of CAF that express a novel tumor-related protein prolargin. Upon secretion prolargin is deposited in the TME where its levels positively correlate with patient outcome (HR=0.37; p=0.01). In vivo, tumors with lower prolargin expression display faster progression (5-fold; p=0.01) and stronger angiogenesis. Mechanistically, aggressive HCC cells degrade prolargin using matrix metalloprotease 3 (MMP3). We show that prolargin binds and inhibits several growth factors, key to tumor progression. Inhibiting prolargin degradation combined with sorafenib, demonstrated superior tumor control compared to sorafenib treatment alone. In conclusion, prolargin-expressing CAF have tumor-antagonizing properties. Stabilizing prolargin tumoral levels should be considered for systemic therapy of HCC, involving CAF in existing TME targeting.

cancer biology↗