Analysis of Prrx1-dependent regulation of tumor-associated fibroblasts in pancreatic ductal adenocarcinoma
Final Report Abstract
The ductal adenocarcinoma of the pancreas (PDAC) is a highly aggressive form of cancer characterized by its dense and fibrous desmoplastic stroma. The stromal component of the tumor microenvironment is rich in cancer-associated fibroblasts (CAFs), which can transition between different states such as inactive, inflammatory, and myofibroblastic. These transitions instruct the cellular and biophysical properties of tumors. However, the mechanisms and dynamics of these transitions are not well understood. This project aimed to investigate how CAF plasticity influences the development and progression of PDAC, as well as their role in therapy resistance and the formation of an immunosuppressive microenvironment. In extensive preliminary work, we identified the paired-related homeobox 1 protein (Prrx1) as a plasticity transcription factor in pancreatic cancer cells. However, the role of Prrx1 in CAFs had not been previously studied. To explore the effects of CAF plasticity on PDAC, we developed an endogenous mouse model of PDAC in which the gene for Prrx1 was specifically deleted in the CAF compartment. Additionally, we established several in vitro model systems to conduct co-culture experiments to determine the influence of CAFs on tumor differentiation and chemotherapy response. Our in vivo and in vitro experiments demonstrate that CAFs lacking Prrx1 remain in a constantly hyperactivated state. This persistent activation of CAFs alters tumor progression and differentiation. Moreover, it was found that Prrx1 in CAFs drives metastasis. Interestingly, Prrx1 expression in CAFs also supported an immunosuppressive microenvironment, suggesting a potential mechanism through which Prrx1 promotes cancer growth and metastasis. Furthermore, gene expression analysis revealed that pancreatic cancer patients with high levels of Prrx1 expression in their stroma had the most aggressive form of PDAC, associated with poor patient prognosis. Co-culture experiments with tumor organoids and CAFs showed that CAFs contribute to making PDAC cells resistant to the chemotherapeutic agent gemcitabine by producing hepatocyte growth factor (HGF). To further investigate the reciprocal interaction of tumor cells and CAFs, an in ovo model was developed where PDOs were placed on the chorioallantoic membrane (CAM) of fertilized chicken eggs, allowing for the study of tumorigenesis, stromal remodeling, invasion, and metastasis. In summary, we found that the Prrx1 transcription factor is crucial for regulating CAF activation, enabling to switch between inactive and active states. This study demonstrates that Prrx1-driven plasticity in CAFs plays a significant role in the development, metastasis, and therapy resistance of PDAC.
Publications
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AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53. Gastroenterology, 161(5), 1601-1614.e23.
Zhang, Zhiheng; Li, Hongzhen; Deng, Yibin; Schuck, Kathleen; Raulefs, Susanne; Maeritz, Nadja; Yu, Yuanyuan; Hechler, Torsten; Pahl, Andreas; Fernández-Sáiz, Vanesa; Wan, Yuan; Wang, Guosheng; Engleitner, Thomas; Öllinger, Rupert; Rad, Roland; Reichert, Maximilian; Diakopoulos, Kalliope N.; Weber, Verena; Li, Jingjing ... & Kong, Bo
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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism. EMBO Molecular Medicine, 13(4).
Hartleben, Goetz; Schorpp, Kenji; Kwon, Yun; Betz, Barbara; Tsokanos, Foivos‐Filippos; Dantes, Zahra; Schäfer, Arlett; Rothenaigner, Ina; Monroy, Kuhn José Manuel; Morigny, Pauline; Mehr, Lisa; Lin, Sean; Seitz, Susanne; Tokarz, Janina; Artati, Anna; Adamsky, Jerzy; Plettenburg, Oliver; Lutter, Dominik; Irmler, Martin ... & Berriel, Diaz Mauricio
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HDAC2 Facilitates Pancreatic Cancer Metastasis. Cancer Research, 82(4), 695-707.
Krauß, Lukas; Urban, Bettina C.; Hastreiter, Sieglinde; Schneider, Carolin; Wenzel, Patrick; Hassan, Zonera; Wirth, Matthias; Lankes, Katharina; Terrasi, Andrea; Klement, Christine; Cernilogar, Filippo M.; Öllinger, Rupert; de Andrade, Krätzig Niklas; Engleitner, Thomas; Schmid, Roland M.; Steiger, Katja; Rad, Roland; Krämer, Oliver H.; Reichert, Maximilian ... & Schneider, Günter
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Mesenchymal Plasticity Regulated by Prrx1 Drives Aggressive Pancreatic Cancer Biology. Gastroenterology, 160(1), 346-361.e24.
Feldmann, Karin; Maurer, Carlo; Peschke, Katja; Teller, Steffen; Schuck, Kathleen; Steiger, Katja; Engleitner, Thomas; Öllinger, Rupert; Nomura, Alice; Wirges, Nils; Papargyriou, Aristeidis; Jahan, Sarker Rim Sabrina; Ranjan, Raphela Aranie; Dantes, Zahra; Weichert, Wilko; Rustgi, Anil K.; Schmid, Roland M.; Rad, Roland; Schneider, Günter ... & Reichert, Maximilian
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Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells. Cell Stem Cell, 28(6), 1105-1124.e19.
Breunig, Markus; Merkle, Jessica; Wagner, Martin; Melzer, Michael K.; Barth, Thomas F.E.; Engleitner, Thomas; Krumm, Johannes; Wiedenmann, Sandra; Cohrs, Christian M.; Perkhofer, Lukas; Jain, Gaurav; Krüger, Jana; Hermann, Patrick C.; Schmid, Maximilian; Madácsy, Tamara; Varga, Árpád; Griger, Joscha; Azoitei, Ninel; Müller, Martin ... & Kleger, Alexander
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Phosphoproteomics Identifies PI3K Inhibitor–selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance. Molecular Cancer Therapeutics, 20(12), 2433-2445.
Cintas, Célia; Douche, Thibault; Dantes, Zahra; Mouton-Barbosa, Emmanuelle; Bousquet, Marie-Pierre; Cayron, Coralie; Therville, Nicole; Pont, Frédéric; Ramos-Delgado, Fernanda; Guyon, Camille; Garmy-Susini, Barbara; Cappello, Paola; Burlet-Schiltz, Odile; Hirsch, Emilio; Gomez-Brouchet, Anne; Thibault, Benoît; Reichert, Maximilian & Guillermet-Guibert, Julie
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T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nature Biomedical Engineering, 5(11), 1246-1260.
Lesch, Stefanie; Blumenberg, Viktoria; Stoiber, Stefan; Gottschlich, Adrian; Ogonek, Justyna; Cadilha, Bruno L.; Dantes, Zahra; Rataj, Felicitas; Dorman, Klara; Lutz, Johannes; Karches, Clara H.; Heise, Constanze; Kurzay, Mathias; Larimer, Benjamin M.; Grassmann, Simon; Rapp, Moritz; Nottebrock, Alessia; Kruger, Stephan; Tokarew, Nicholas ... & Kobold, Sebastian
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Accurate prediction of histological grading of intraductal papillary mucinous neoplasia using deep learning. Endoscopy, 55(05), 415-422.
Schulz, Dominik; Heilmaier, Markus; Phillip, Veit; Treiber, Matthias; Mayr, Ulrich; Lahmer, Tobias; Mueller, Julius; Demir, Ihsan Ekin; Friess, Helmut; Reichert, Maximilian; Schmid, Roland M. & Abdelhafez, Mohamed
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Detecting drug resistance in pancreatic cancer organoids guides optimized chemotherapy treatment. The Journal of Pathology, 257(5), 607-619.
Hennig, Alexander; Baenke, Franziska; Klimova, Anna; Drukewitz, Stephan; Jahnke, Beatrix; Brückmann, Sascha; Secci, Ramona; Winter, Christof; Schmäche, Tim; Seidlitz, Therese; Bereuter, Jean‐Paul; Polster, Heike; Eckhardt, Lisa; Schneider, Sidney A.; Brückner, Stefan; Schmelz, Renate; Babatz, Jana; Kahlert, Christoph; Distler, Marius ... & Stange, Daniel E.
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Epigenetic drug screening defines a PRMT5 inhibitor–sensitive pancreatic cancer subtype. JCI Insight, 7(10).
Orben, Felix; Lankes, Katharina; Schneeweis, Christian; Hassan, Zonera; Jakubowsky, Hannah; Krauß, Lukas; Boniolo, Fabio; Schneider, Carolin; Schäfer, Arlett; Murr, Janine; Schlag, Christoph; Kong, Bo; Öllinger, Rupert; Wang, Chengdong; Beyer, Georg; Mahajan, Ujjwal M.; Xue, Yonggan; Mayerle, Julia; Schmid, Roland M. ... & Schneider, Günter
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Identification of treatment‐induced vulnerabilities in pancreatic cancer patients using functional model systems. EMBO Molecular Medicine, 14(4).
Peschke, Katja; Jakubowsky, Hannah; Schäfer, Arlett; Maurer, Carlo; Lange, Sebastian; Orben, Felix; Bernad, Raquel; Harder, Felix N.; Eiber, Matthias; Öllinger, Rupert; Steiger, Katja; Schlitter, Melissa; Weichert, Wilko; Mayr, Ulrich; Phillip, Veit; Schlag, Christoph; Schmid, Roland M.; Braren, Rickmer F.; Kong, Bo ... & Reichert, Maximilian
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Indirect targeting of MYC sensitizes pancreatic cancer cells to mechanistic target of rapamycin (mTOR) inhibition. Cancer Communications, 42(4), 360-364.
Schneeweis, Christian; Hassan, Zonera; Ascherl, Katja; Wirth, Matthias; Koutsouli, Stella; Orben, Felix; Krauß, Lukas; Schneider, Carolin; Öllinger, Rupert; Krämer, Oliver H.; Rad, Roland; Reichert, Maximilian; Robles, Maria S.; Saur, Dieter & Schneider, Günter
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Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids. Nature Communications, 13(1).
Randriamanantsoa, S.; Papargyriou, A.; Maurer, H. C.; Peschke, K.; Schuster, M.; Zecchin, G.; Steiger, K.; Öllinger, R.; Saur, D.; Scheel, C.; Rad, R.; Hannezo, E.; Reichert, M. & Bausch, A. R.
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In-vitro model to mimic T cell subset change in human PDAC organoid co-culture. Journal of Cancer Research and Clinical Oncology, 149(14), 13051-13064.
Knoblauch, M.; Ma, T.; Beirith, I.; Koch, D.; Hofmann, F.; Heinrich, K.; Aghamaliev, U.; Sirtl, S.; Westphalen, C. B.; Nieß, H.; Reichert, M.; Angele, M. K.; Regel, I.; Bazhin, A. V.; Werner, J.; Ilmer, M. & Renz, Bernhard W.
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Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer. Cell Reports, 42(6), 112533.
Saini, Massimo; Schmidleitner, Laura; Moreno, Helena Domínguez; Donato, Elisa; Falcone, Mattia; Bartsch, Johanna M.; Klein, Corinna; Vogel, Vanessa; Würth, Roberto; Pfarr, Nicole; Espinet, Elisa; Lehmann, Mareike; Königshoff, Melanie; Reitberger, Manuel; Haas, Simon; Graf, Elisabeth; Schwarzmayr, Thomas; Strom, Tim-Matthias; Spaich, Saskia ... & Scheel, Christina H.
