Duale Rekombinasesysteme zur Entwicklung von Kombinationstherapien für das Pankreaskarzinom
Zusammenfassung der Projektergebnisse
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly lethal. The mesenchymal PDAC subtype displays a particular worse prognosis and is characterized by an increased gene dosage and expression of oncogenic KRAS. It is highly immunosuppressive and resistant to polychemotherapies, targeted therapies and immune checkpoint blockade, representing an unmet clinical need. We screened 50 human and 250 mouse PDAC cell cultures with over 400 drugs to identify subtype-specific vulnerabilities and determinants of drug sensitivity. We identified MEK inhibitors as on of the top hits, inducing a strong cytostatic effect in classical lines, while mesenchymal ones showed strong resistance. A high-throughput drug screen of 418 compounds with the MEK inhibitor trametinib (T) identified nintedanib (N) as a synergistic partner, selectively effective in mesenchymal PDAC. Combined treatment (T/N) induced cell cycle arrest and death specifically in mesenchymal cells, while some classical lines responded antagonistically. In vivo, T/N treatment significantly reduced tumor volume and doubled survival in mesenchymal PDAC models. Classical tumors also responded, though primarily due to trametinib alone. T/N treatment led to major changes in the TME, notably a marked increase in activated CD8+ T cells in mesenchymal tumors. In classical tumors, immune exclusion remained, with T cells restricted to the tumor margins. Macrophage polarization shifted from M2 to M1-like states in both subtypes, while neutrophil recruitment increased only in classical tumors. We then tested whether T cell infiltration sensitized tumors to checkpoint inhibitors. Adding anti–PD-L1 to T/N therapy significantly improved survival in mesenchymal PDAC. Single-cell RNA sequencing revealed that T/N treatment induced DNA damage, interferon signaling, and enhanced antigen presentation in mesenchymal tumors. T cells displayed strong cytotoxic and effector gene signatures, which increased further with anti–PD-L1 immune checkpoint blockade. In classical tumors, cytotoxic CD8+ T cells were reduced along with regulatory T cells. Secretome analysis showed that the T/N therapy downregulated immunosuppressive cytokines (e.g., CCL2, CSF1) and upregulated T cell–recruiting chemokines (e.g., CXCL16, CXCL12) in mesenchymal tumors. In conclusion, reprogramming the TME of immunologically cold mesenchymal PDAC by T/N treatment enables effective immune responses. Combining T/N with anti–PD-L1 offers a promising therapeutic strategy for this otherwise untreatable PDAC subtype.
Projektbezogene Publikationen (Auswahl)
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Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component. EMBO Molecular Medicine, 13(7).
Thibault, Benoit; Ramos‐Delgado, Fernanda; Pons‐Tostivint, Elvire; Therville, Nicole; Cintas, Celia; Arcucci, Silvia; Cassant‐Sourdy, Stephanie; Reyes‐Castellanos, Gabriela; Tosolini, Marie; Villard, Amelie V.; Cayron, Coralie; Baer, Romain; Bertrand‐Michel, Justine; Pagan, Delphine; Ferreira Da Mota, Dina; Yan, Hongkai; Falcomatà, Chiara; Muscari, Fabrice; Bournet, Barbara ... & Guillermet‐Guibert, Julie
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Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Nature Cancer, 3(3), 318-336.
Falcomatà, Chiara; Bärthel, Stefanie; Widholz, Sebastian A.; Schneeweis, Christian; Montero, Juan José; Toska, Albulena; Mir, Jonas; Kaltenbacher, Thorsten; Heetmeyer, Jeannine; Swietlik, Jonathan J.; Cheng, Jing-Yuan; Teodorescu, Bianca; Reichert, Oliver; Schmitt, Constantin; Grabichler, Kathrin; Coluccio, Andrea; Boniolo, Fabio; Veltkamp, Christian; Zukowska, Magdalena ... & Saur, Dieter
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Syngeneic Mouse Orthotopic Allografts to Model Pancreatic Cancer. Journal of Visualized Experiments(188).
Schmitt, Constantin; Saur, Dieter; Bärthel, Stefanie & Falcomatà, Chiara
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Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation. Nature Communications, 14(1).
Swietlik, Jonathan J.; Bärthel, Stefanie; Falcomatà, Chiara; Fink, Diana; Sinha, Ankit; Cheng, Jingyuan; Ebner, Stefan; Landgraf, Peter; Dieterich, Daniela C.; Daub, Henrik; Saur, Dieter & Meissner, Felix
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Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer. Cancer Discovery, 13(2), 278-297.
Falcomatà, Chiara; Bärthel, Stefanie; Schneider, Günter; Rad, Roland; Schmidt-Supprian, Marc & Saur, Dieter
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Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy. Nature Cancer, 4(4), 454-467.
Bärthel, Stefanie; Falcomatà, Chiara; Rad, Roland; Theis, Fabian J. & Saur, Dieter
