The inflammatory micromilieu: decisive role in tumor plasticity in pancreatic cancer

• Applicant: Professor Dr. Matthias Gaida
• Subject Area: Pathology
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321664872

• Final Report Year: 2024

Final Report Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor characterized by a very distinct microenvironment, marked hypoxia, interaction with various non-neopaltic “host” cells, infiltrative growth, and high heterogeneity and plasticity. The research conducted during the recent funding period indicated that intratumor hypoxia induces the transcription factor Blimp1, which generates an aggressive tumor phenotype. Various correlative studies of molecular pathology and clinical imaging have shown that these particularly aggressive tumors, characterized by enhanced Blimp1 expression, hypoxia, pronounced stromal desmoplasia, epithelial-to-mesenchymal transition, and tumor budding, can already be identified and stratified using clinically implemented routine imaging. Building on this data, several software-supported, artificial intelligence-based algorithms were subsequently developed that can identify anatomical, benign and malignant structures in pancreatic tissue and liver metastases. Based on analyses of the tumor microenvironment, novel data were generated which further confirm that in particular Th17 cells induce an aggressive tumor phenotype in pancreatic cancer. Finally, the interaction of the pancreatic carcinoma with the anatomically surrounding fat tissue was studied. The analysis demonstrated that ADAMTS13, induced by adipose tissue in pancreatic carcinoma is significantly involved in the neoangiogenesis, migration, and invasion of tumor cells. All of these generated data show and illustrate a pronounced interaction of pancreatic cancer with the tumor microenvironment and provide derivable diagnostic and therapeutic implications.

Publications

• Diffusion Kurtosis Imaging—A Superior Approach to Assess Tumor–Stroma Ratio in Pancreatic Ductal Adenocarcinoma. Cancers, 12(6), 1656.
  Mayer, Philipp; Jiang, Yixin; Kuder, Tristan A.; Bergmann, Frank; Khristenko, Ekaterina; Steinle, Verena; Kaiser, Jörg; Hackert, Thilo; Kauczor, Hans-Ulrich; Klauß, Miriam & Gaida, Matthias M.
  
• Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging in Pancreatic Cancer is Associated with Tumor Hypoxia. Cancers, 13(1), 89.
  Mayer, Philipp; Kraft, Anne; Witzel, Hagen R.; Marnet, Nicole; Hörner, Nina; Roth, Wilfried; Heinrich, Stefan; Hackert, Thilo; Bergmann, Frank; Kauczor, Hans-Ulrich; Klauss, Miriam & Gaida, Matthias M.
  
• The Microarchitecture of Pancreatic Cancer as Measured by Diffusion-Weighted Magnetic Resonance Imaging Is Altered by T Cells with a Tumor Promoting Th17 Phenotype. International Journal of Molecular Sciences, 21(1), 346.
  Mayer, Philipp; Linnebacher, Alica; Glennemeier-Marke, Hannah; Marnet, Nicole; Bergmann, Frank; Hackert, Thilo; Klauss, Miriam; Poth, Tanja & Gaida, Matthias M.
  
• Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion. Modern Pathology, 33(4), 639-647.
  Hong, Seung-Mo; Jung, DongJun; Kiemen, Ashley; Gaida, Matthias M.; Yoshizawa, Tadashi; Braxton, Alicia M.; Noë, Michaël; Lionheart, Gemma; Oshima, Kiyoko; Thompson, Elizabeth D.; Burkhart, Richard; Wu, Pei-Hsun; Wirtz, Denis; Hruban, Ralph H. & Wood, Laura D.
  
• Deep Learning in Pancreatic Tissue: Identification of Anatomical Structures, Pancreatic Intraepithelial Neoplasia, and Ductal Adenocarcinoma. International Journal of Molecular Sciences, 22(10), 5385.
  Kriegsmann, Mark; Kriegsmann, Katharina; Steinbuss, Georg; Zgorzelski, Christiane; Kraft, Anne & Gaida, Matthias M.
  
• Die Mikroarchitektur des Pankreaskarzinoms aus Sicht des Pathologen und des Radiologen. Der Pathologe, 42(5), 524-529.
  Mayer, Philipp & Gaida, Matthias M.
  
• Epithelial-to-Mesenchymal Transition in Pancreatic Cancer is associated with Restricted Water Diffusion in Diffusion-Weighted Magnetic Resonance Imaging. Journal of Cancer, 12(24), 7488-7497.
  Mayer, Philipp; Kraft, Anne; Roth, Wilfried; Hackert, Thilo; Bergmann, Frank; Kauczor, Hans-Ulrich; Steinle, Verena; Khristenko, Ekaterina; Klauss, Miriam & Gaida, Matthias M.
  
• The effect of surgical suture material on osteoclast generation and implant-loosening. International Journal of Medical Sciences, 18(2), 295-303.
  Dapunt, Ulrike; Prior, Birgit; Kretzer, Jan Philippe; Hänsch, Gertrud Maria & Gaida, Matthias Martin
  
• TNF plays a crucial role in inflammation by signaling via T cell TNFR2. Proceedings of the National Academy of Sciences, 118(50).
  Alam, Muhammad S.; Otsuka, Shizuka; Wong, Nathan; Abbasi, Aamna; Gaida, Matthias M.; Fan, Yu; Meerzaman, Daoud & Ashwell, Jonathan D.
  
• Potential role of the bitter taste receptor T2R14 in the prolonged survival and enhanced chemoresponsiveness induced by apigenin. International Journal of Oncology, 62(1).
  Stern, Louisa; Boehme, Lukas; Goetz, Mara; Nitschke, Christine; Giannou, Anastasios; Zhang, Tao; Güngör, Cenap; Reeh, Matthias; Izbicki, Jakob; Fliegert, Ralf; Hausen, Anne; Giese, Nathalia; Hackert, Thilo; Niv, Masha; Heinrich, Stefan; Gaida, Matthias & Ghadban, Tarik
  
• Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer. Cancer Discovery, 12(8), 1984-2005.
  Fonteneau, Guillaume; Redding, Alexandra; Hoag-Lee, Hannah; Sim, Edward S.; Heinrich, Stefan; Gaida, Matthias M. & Grabocka, Elda
  
• Tumor and stroma COL8A1 secretion induces autocrine and paracrine progression signaling in pancreatic ductal adenocarcinoma. Matrix Biology, 114, 84-107.
  Yan, Bin; Liu, Li; Zhao, Lian; Hinz, Ulf; Luo, Yiqiao; An, Xuefeng; Gladkich, Jury; de la Torre, Carolina; Huang, Zhenhua; Schrapel, Daniel; Gross, Wolfgang; Fortunato, Franco; Schaefer, Michael; Gaida, Matthias M. & Herr, Ingrid
  
• IL-17A-producing CD8+T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts. Gut, 72(8), 1510-1522.
  Picard, Felix Simon Ruben; Lutz, Veronika; Brichkina, Anna; Neuhaus, Felix; Ruckenbrod, Teresa; Hupfer, Anna; Raifer, Hartmann; Klein, Matthias; Bopp, Tobias; Pfefferle, Petra Ina; Savai, Rajkumar; Prinz, Immo; Waisman, Ari; Moos, Sonja; Chang, Hyun-Dong; Heinrich, Stefan; Bartsch, Detlef K.; Buchholz, Malte; Singh, Shiv; ... & Huber, Magdalena
  
• Implementation of deep learning in liver pathology optimizes diagnosis of benign lesions and adenocarcinoma metastasis. Clinical and Translational Medicine, 13(7).
  Kriegsmann, Mark; Kriegsmann, Katharina; Steinbuss, Georg; Zgorzelski, Christiane; Albrecht, Thomas; Heinrich, Stefan; Farkas, Stefan; Roth, Wilfried; Dang, Hien; Hausen, Anne & Gaida, Matthias M.
  
• Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion. Journal of Clinical Investigation, 133(8).
  Jeong, Yea Ji; Knutsdottir, Hildur; Shojaeian, Fatemeh; Lerner, Michael G.; Wissler, Maria F.; Henriet, Elodie; Ng, Tammy; Datta, Shalini; Navarro-Serer, Bernat; Chianchiano, Peter; Kinny-Köster, Benedict; Zimmerman, Jacquelyn W.; Stein-O.’Brien, Genevieve; Gaida, Matthias M.; Eshleman, James R.; Lin, Ming-Tseh; Fertig, Elana J.; Ewald, Andrew J.; Bader, Joel S. & Wood, Laura D.
  
• Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer. Gastroenterology, 165(4), 891-908.e14.
  Yousuf, Suhail; Qiu, Mengjie; Voith von Voithenberg, Lena; Hulkkonen, Johannes; Macinkovic, Igor; Schulz, Axel R.; Hartmann, Domenic; Mueller, Florian; Mijatovic, Margarete; Ibberson, David; AlHalabi, Karam T.; Hetzer, Jenny; Anders, Simon; Brüne, Bernhard; Mei, Henrik E.; Imbusch, Charles D.; Brors, Benedikt; Heikenwälder, Mathias; Gaida, Matthias M.; ... & Roth, Susanne
  
• Reciprocal crosstalk between Th17 and mesothelial cells promotes metastasis‐associated adhesion of ovarian cancer cells. Clinical and Translational Medicine, 14(4).
  Neuhaus, Felix; Lieber, Sonja; Shinkevich, Veronika; Steitz, Anna Mary; Raifer, Hartmann; Roth, Kathrin; Finkernagel, Florian; Worzfeld, Thomas; Burchert, Andreas; Keber, Corinna; Nist, Andrea; Stiewe, Thorsten; Reinartz, Silke; Beutgen, Vanessa M.; Graumann, Johannes; Pauck, Kim; Garn, Holger; Gaida, Matthias; Müller, Rolf & Huber, Magdalena
  
• The radiomorphological appearance of the invasive margin in pancreatic cancer is associated with tumor budding. Langenbeck's Archives of Surgery, 409(1).
  Mayer, Philipp; Hausen, Anne; Steinle, Verena; Bergmann, Frank; Kauczor, Hans-Ulrich; Loos, Martin; Roth, Wilfried; Klauss, Miriam & Gaida, Matthias M.