Multi-omics data integration and modeling unravels new mechanisms for pancreatic cancer and improves prognostic prediction

Pancreatic ductal adenocarcinoma (PDAC), has recently been found to be a heterogeneous disease, although the extension of its diversity remains to be fully understood. Here, we harmonize transcriptomic profiles derived from both PDAC epithelial and microenvironment cells to develop a Master Regulators (MR)-Gradient model that allows important inferences on transcriptional networks, epigenomic states, and metabolomics pathways that underlies this disease heterogeneity. This gradient model was generated by applying a blind source separation based on independent components analysis and robust principal component analyses (RPCA), following regulatory network inference. The result of these analyses reveals that PDAC prognosis strongly associates with the tumor epithelial cell phenotype and the immunological component. These studies were complemented by integration of methylome and metabolome datasets generated from patient-derived xenograft (PDX), together experimental measurements of metabolites, immunofluorescence microscopy, and western blot. At the metabolic level, PDAC favorable phenotype showed a positive correlation with enzymes implicated in complex lipid biosynthesis. In contrast, the unfavorable phenotype displayed an augmented OXPHOS independent metabolism centered on the Warburg effect and glutaminolysis. Epigenetically, we find that a global hypermethylation profile associates with the worst prognosis. Lastly, we report that, two antagonistic histone code writers, SUV39H1/SUV39H2 (H3K9Me3) and KAT2B (H3K9Ac) were identified key deregulated pathways in PDAC. Our analysis suggests that the PDAC phenotype, as it relates to prognosis, is determined by a complex interaction of transcriptomic, epigenomic, and metabolic features. Furthermore, we demonstrated that PDAC prognosis could be modulated through epigenetics

Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial–mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phe�notype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the transla�tional activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsivenes

Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib. Experimental Design: First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids. Results: Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial–mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity. Conclusions: We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness. </jats:sec

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

AbstractRecent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.</jats:p

Supplementary Figure S1 from Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

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Video S2 from Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

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Supplementary Table S2 from Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

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Supplementary Figure S2 from Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib

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