TRR 417:  Cellular Communication in the Stroma of Colorectal Cancer: From Pathophysiology to Clinical Translation

• Subject Area: Medicine ; Biology
• Term: since 2025
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540805631

Colorectal carcinogenesis is a prime example illustrating that tumor evolution, beyond the presence of critical mutations in intestinal stem cells, heavily relies on the interaction between mutagenized epithelial cells and the tumor microenvironment (TME), which profoundly influences every stage of tumor development. Crucially, the bidirectional communication between tumor epithelia and the TME is essential not only for all phases of tumorigenesis but also plays a significant role in individual responses to cancer therapies. Yet, most current treatment protocols still focus on eliminating mutated tumor cells without accounting for the TME’s contributions. Improved combinatorial and multi-modal therapies could offer better outcomes, which are desperately needed given the disease’s dismal five-year survival rate of just 64%. To address this critical unmet need, we aim to form an interdisciplinary Collaborative Research Center/Transregio (TRR). Our goal is to develop a comprehensive understanding of the functional role of the colorectal TME in CRC biology and therapy response. Beyond its scientific objectives, the TRR aims to train the next generation of clinician-scientists, providing early-career researchers with the opportunity to establish long-term careers in colorectal cancer research in Germany, extending beyond the twelve years of funding. Our hypothesis is that a deep understanding of the cellular and molecular mechanisms within the TME will lead to novel translational strategies targeting the TME, enhancing current therapies and making immunotherapy viable for microsatellite-stable CRC. The infrastructure and conceptual foundation for this TRR have been laid by the previously funded RU 2438, which has established preclinical models (including animal models and patient-derived organoid systems) and technologies harmonized across all three applicant universities. Building on this success, the TRR has selected leading scientists with expertise in emerging research areas to lead projects in collaboration with translational and clinical CRC experts. The TRR aims to perform groundbreaking basic research that will enable evaluation in clinical studies associated with the consortium. The participating scientists have been selected from universities affiliated with the Oncology Centers of Excellence (Onkologische Spitzenzentren) supported by the Deutsche Krebshilfe, the German Cancer Consortium (DKTK), the Bavarian Center for Cancer Research (BZKF), and the recently expanded National Center for Tumor Diseases (NCT). By bringing together experts from these institutions in basic and translational CRC research, the TRR will establish a unique center of excellence for CRC research in Germany. Targeting the TME for CRC therapy is a timely and promising approach that holds the potential for innovative strategies to improve the outcomes of the many patients who are currently facing a poor prognosis.

• DFG Programme: CRC/Transregios

Current projects

• MGKIRTG - Integrated Research Training Group (Project Heads Farin, Henner ;  Feuerstein, Ph.D., Reinhild ;  Günther, Claudia )
• P01 - Modulating CAF plasticity to enable immunotherapy of colorectal cancer (Project Head Greten, Florian R. )
• P02 - Multi modal prediction of therapy response for rectal cancer patients (Project Heads Buettner, Ph.D., Florian ;  Flinner, Nadine )
• P03 - Metastasis predisposing extracellular matrix architecture in colorectal cancer (Project Heads Briquez, Ph.D., Priscilla ;  Fichtner-Feigl, Stefan ;  Reuten, Raphael )
• P04 - Mapping the CAF subtype-dependent reciprocal signaling in the CRC niche (Project Heads Farin, Henner ;  Stemmler, Marc )
• P05 - The role of LIFR signaling in CAFs in CRC (Project Head Neufert, Ph.D., Clemens )
• P06 - Impact of vascular plasticity on therapy responses in CRC (Project Heads Günther, Claudia ;  Naschberger, Elisabeth )
• P07 - Specific role(s) of the inflammasome in the TME of primary and metastasized sporadic CRC (Project Heads Berlin, Ph.D., Christopher ;  Groß, Olaf )
• P08 - The role of IL-38 in shaping tumor-promoting versus protective inflammation in colorectal cancer (Project Head Weigert, Andreas )
• P09 - Unraveling the Role of Stromal IL-36R Signaling in Colorectal Tumorigenesis (Project Heads Koop, Kristina ;  Neurath, Markus F. )
• P10 - Targeting the intra-metastatic microbiome in colorectal cancer (Project Heads Bengsch, Ph.D., Bertram ;  Feuerstein, Ph.D., Reinhild )
• P11 - Role of microbial amino acid metabolism on chemotherapy response in CRC (Project Heads Arkan, Ph.D., Melek Canan ;  Tatarova, Zuzana )
• P12 - Identification of immunomodulatory microbial metabolites as novel therapeutics for advanced CRC (Project Head Rosshart, Stephan Patrick )
• P13 - Modulation of CRC development and progressi- on by GPR15L-dependent effects on lymphocyte infiltration and the intestinal microbiota (Project Heads Müller, Tanja ;  Zundler, Sebastian )
• P14 - The role of gamma/delta T cells in the tumor microenvironment of CRC (Project Heads Kesselring, Rebecca ;  Minguet, Ph.D., Susana )
• P15 - Tumor stroma-derived signals impair cDC1-dependent checkpoint inhibition as a potential resistance mechanism of colorectal cancer immunotherapy (Project Head Hildner, Kai )
• P16 - The role of primary-CRC-derived adaptive immune cells in anti-metastasis immunity (Project Heads Fichtner-Feigl, Stefan ;  Imkeller, Katharina )
• P17 - STAT3-controlled cross-dressing of dendritic cells in anti-tumor immunity (Project Head Ziegler, Ph.D., Paul K. )
• P18 - Identifying and overcoming CAR T cell barriers in the colorectal carcinoma microenvironment (Project Heads Buchholz, Christian ;  Farin, Henner )
• P19 - Targeting colorectal liver metastasis by overcoming MYC induced immune evasion (Project Head Wiegering, Armin )
• S01 - Human tumor organoid biobanks for preclinical validation (Project Heads Berlin, Ph.D., Christopher ;  Greten, Florian R. ;  Naschberger, Elisabeth )
• S02 - Spatial profiling of the tumor microenvironment in CRC (Project Heads Reiss, Yvonne ;  Ritter, Birgit )
• S03 - Research Information Infrastructure, Research Data Management and Bioinformatics Core (Project Heads Börries, Melanie ;  Gupta, Pooja )
• Z - Central tasks of the collaborative research centre (Project Head Greten, Florian R. )

• Applicant Institution: Goethe-Universität Frankfurt am Main
• Co-Applicant Institution: Albert-Ludwigs-Universität Freiburg; Friedrich-Alexander-Universität Erlangen-Nürnberg
• Participating Institution: Georg-Speyer-Haus; Institut für Tumorbiologie und experimentelle Therapie
• Business and Industry: Paul-Ehrlich-Institut; Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
• Spokesperson: Professor Dr. Florian R. Greten