Biology subjects

Van Laethem, J.-L.

Publications and source records attributed to Van Laethem, J.-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

Spatial map of native duct cell populations in human pancreas and their representation in pancreatic cancers

BackgroundA resemblance of pancreatic tumors to their native tissue architecture remains largely unexplored, while it may reveal novel insights into the healthy and diseased tissue. ObjectiveThis study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumors, i.e. pancreatic ductal adenocarcinoma (PDAC) and adenosquamous cancer of the pancreas (ASCP). DesignNew datasets were acquired with several spatial transcriptomics platforms and were integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. ResultsGroups of Keratin-5+ cells in larger ducts have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. At single cell resolution, this group comprises {Delta}Np63+ basal cells (BAS) and {Delta}Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16. Additionally, we identified three other luminal cell populations in the ducts (LUM-A, -C, -D). In cancer, BAS and LUM-B signatures associate with basal-like (BL) PDAC, and correlate with lower survival. However, PDAC exhibits a random spatial pattern and fragmented native expression programs while ASCP preserve the identity of LUM-B and BAS in a spatially unmixed pattern. {Delta}Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. ConclusionSpatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumor identities. This warrants a separate consideration in research and therapy. What is already known on this topicWhile tumors in the pancreas can exhibit basal-like and squamous features resembling tumors of other tissues, their resemblance to the native duct cells, and possible subpopulations thereof, had not been studied in detail. What this study addsOne basal and four luminal spatially distinct cell populations exist in human pancreatic ducts. These are best conserved in ASCP while PDAC shows loss of the native cell identity program. How this study might affect research, practice or policyOur study demonstrates fundamental differences between the tumor cells of the BL PDAC versus the rare ASCP, highlighting the necessity for a clear distinction between them in research and in tumor-specific treatments. Meanwhile, the research community should acknowledge the spatial and functional heterogeneity of human duct cells, including in their experimental models.

cancer 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↗

bioRxiv2023

No evidence for the presence and control of tumor growth by cytoplasmic stress granules in pancreatic cancer

Cytoplasmic stress granules (SG) are attracting growing attention in cancer research1. As such, a study published in Cell2 has certainly served as a trigger for this trend which currently asserts that SG are a relevant therapeutic target. Here, we would like to express a warning about the conclusions of this article, as well as of the subsequent study3, and more generally on a methodological approach frequently used in research studying SG in cancer and which we believe to be misleading.

cancer biology↗