Priming therapy by targeting enhancer-initiated pathways in patient-derived pancreatic cancer cellsResearch in context
Nicolas A. Fraunhoffer,
Aura I. Moreno Vega,
Analía Meilerman Abuelafia,
Marie Morvan,
Emilie Lebarbier,
Tristan Mary-Huard,
Michael Zimmermann,
Gwen Lomberk,
Raul Urrutia,
Nelson Dusetti,
Yuna Blum,
Remy Nicolle,
Juan Iovanna
Affiliations
Nicolas A. Fraunhoffer
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France; Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Facultad de Medicina, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina
Aura I. Moreno Vega
Tumour Identity Card Program (CIT), French League Against Cancer, Paris, France
Analía Meilerman Abuelafia
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
Marie Morvan
Laboratoire Modal'X - UMR 9023, Université Paris Nanterre, Nanterre, France
Emilie Lebarbier
Laboratoire Modal'X - UMR 9023, Université Paris Nanterre, Nanterre, France; Université Paris-Saclay, AgroParisTech, INRAE, UMR MIA Paris-Saclay, Palaiseau 91120, France
Tristan Mary-Huard
Université Paris-Saclay, AgroParisTech, INRAE, UMR MIA Paris-Saclay, Palaiseau 91120, France
Michael Zimmermann
Genomics and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA; Division of Research, Department of Surgery, Medical College of Wisconsin, Center, Milwaukee, WI, USA
Gwen Lomberk
Genomics and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA; Division of Research, Department of Surgery, Medical College of Wisconsin, Center, Milwaukee, WI, USA
Raul Urrutia
Genomics and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI, USA; Division of Research, Department of Surgery, Medical College of Wisconsin, Center, Milwaukee, WI, USA
Nelson Dusetti
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
Yuna Blum
Univ Rennes, CNRS, INSERM, IGDR (Institut de Génétique et Développement de Rennes) - UMR 6290, ERL U1305, Rennes, France
Remy Nicolle
Tumour Identity Card Program (CIT), French League Against Cancer, Paris, France; Université Paris Cité, Centre de Recherche sur l'Inflammation (CRI), INSERM, U1149, CNRS, ERL 8252, Paris F-75018, France
Juan Iovanna
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France; Hospital de Alta Complejidad El Cruce, Florencio Varela, BA, Argentina; University Arturo Jauretche, Florencio Varela, BA, Argentina; Corresponding author. Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
Summary: Background: Systems biology leveraging multi-OMICs technologies, is rapidly advancing development of precision therapies and matching patients to targeted therapies, leading to improved responses. A new pillar of precision oncology lies in the power of chemogenomics to discover drugs that sensitizes malignant cells to other therapies. Here, we test a chemogenomic approach using epigenomic inhibitors (epidrugs) to reset patterns of gene expression driving the malignant behavior of pancreatic tumors. Methods: We tested a targeted library of ten epidrugs targeting regulators of enhancers and super-enhancers on reprogramming gene expression networks in seventeen patient-derived primary pancreatic cancer cell cultures (PDPCCs), of both basal and classical subtypes. We subsequently evaluated the ability of these epidrugs to sensitize pancreatic cancer cells to five chemotherapeutic drugs that are clinically used for this malignancy. Findings: To comprehend the impact of epidrug priming at the molecular level, we evaluated the effect of each epidrugs at the transcriptomic level of PDPCCs. The activating epidrugs showed a higher number of upregulated genes than the repressive epidrugs (χ2 test p-value <0.01). Furthermore, we developed a classifier using the baseline transcriptome of epidrug-primed-chemosensitized PDPCCs to predict the best epidrug-priming regime to a given chemotherapy. Six signatures with a significant association with the chemosensitization centroid (R ≤ −0.80; p-value < 0.01) were identified and validated in a subset of PDPCCs. Interpretation: We conclude that targeting enhancer-initiated pathways in patient-derived primary cells, represents a promising approach for developing new therapies for human pancreatic cancer. Funding: This work was supported by INCa (Grants number 2018-078 to ND and 2018- 079 to JI), Canceropole PACA (ND), Amidex Foundation (ND), and INSERM (JI).
