How do tumors develop and why can they spread? What strategies do the mutated cells use to circumvent the body's protective mechanisms, multiply and ultimately lead to cancer? A research alliance of renowned institutions from Cambridge (Great Britain), Daejeon (South Korea) and Dresden is working to shed some light on the origin of clonal pathogenesis with the joint project "ClonEScape". The aim is to use the findings to provide innovative approaches for the detection, treatment and prevention of cancer at an early stage. For this project, the scientists Prof. Benjamin Simons (University of Cambridge), Dr. Maria Alcolea (University of Cambridge), Dr. Bon-Kyoung Koo (Institute for Basic Science) and Prof. Daniel Stange (TU Dresden) have been awarded the prestigious Synergy Grant of the European Research Council (ERC) alongside funding amounting to almost EUR 10M.

Epithelial tissue comprises sheets of cells that cover all internal and external body surfaces - for example, the skin is made up of epithelial cells, as are the mucous membranes of the gastrointestinal tract. They play a central role in protecting our bodies from external influences and must constantly renew themselves in order to repair damage. Tumors usually develop through a process beginning with field carcinogenesis, i.e. mutated cancer cells multiply through division and, in turn, join together to form smaller clusters or tumor cell clones, within normal-looking tissue. To prevent them from spreading, epithelial tissues have developed protective mechanisms that inhibit the growth of these clones. At the same time, however, they must have time for their necessary regeneration. The early tumor cell clones seem to take advantage of this downtime as a kind of loophole. If the initial tumor cell clones outsmart these protective barriers, a malignant tumor develops over time.

© ClonEScape

How exactly the protective mechanisms are thwarted and how the tumor cells then multiply and spread unchecked is the central concern of the international research alliance "ClonEScape". Its focus is on the epithelia of the gastrointestinal tract and how injury, inflammation and aging facilitate the development of cancer cells, allowing them to evade the natural protective mechanisms of these cell sheets.

© Uniklinikum Dresden / Gabriele Bellmann

"Over the next six years, the research group will strive to gain a better understanding of the cellular and molecular mechanisms that lead to initial tumor development and to develop potential preventative and therapeutic approaches," explains Prof. Daniel Stange, physician and scientist at the University Hospital Dresden, TUD’s Faculty of Medicine and the National Center for Tumor Diseases (NCT/UCC) in Dresden.

The scientists will achieve this goal by combining various experimental methods and mathematical models. This should make it possible to decipher the mechanisms that control the growth of mutated cancer cells in an environment of otherwise healthy cells. Advanced techniques such as genetic barcoding, single-cell genomics and spatial transcriptomics are used to trace the lineage and dynamics of mutated clones. The aim is to identify the genetic mechanisms that regulate cell competition and allow the mutated clones to surpass natural growth limits. Through genetic manipulation of 3D organoid cultures using CRISPR/Cas9 and detailed somatic SNV-based lineage analyses, the scientists also want to investigate the extent to which these principles hold true between human and murine model systems. The results should provide new therapeutic approaches which allow for the prevention, early detection as well as the impediment of tumor formation, also due to any age-related tissue changes. 

In summary, the study aims to better understand the clonal pathogenesis of tumors in different tissues. It is divided into three complementary objectives:

• Understanding the dynamics of tumor clones: The spread of mutated tumor cell clones is quantified in order to analyze how they compete with neighboring "healthy" cell clones.
• Analyzing the influence of aging and injuries: The researchers investigate how aging processes and injuries can influence competition between cells and contribute to cancer formation.
• Investigating h a transfer to human tissue: The mechanisms of clonal pathogenesis will also be studied in human tissues.

"The ERC Synergy Grant is one of the most prestigious science prizes in Europe and is only awarded to outstanding research projects that have the potential to achieve real breakthroughs," congratulates Prof. Esther Troost, Dean of the Faculty of Medicine of TU Dresden: "With ClonEScape, the researchers are delving deep into the depths of carcinogenesis. This award not only underlines the importance of this project, but also draws attention to the expertise in cancer research in Dresden as a scientific location."

Prof. Michael Albrecht, Medical Director of the University Hospital of Dresden, adds: "If we understand better how and why tumors develop, we can intervene earlier, provide more targeted treatment and significantly improve the chances of recovery for our patients. We thrilled that Dresden was able to receive this prestigious funding."

The ERC Synergy Grants
The ERC Synergy Grants of the European Research Council (ERC) support teams of two to four individual researchers working at different locations. In this way, support is provided to projects that are characterized by intensive interdisciplinary collaboration – which is the only way they can be tackled at all. The grant is endowed with up to EUR 10 million plus possible investments over a period of six years. As for the ClonEScape project, the funding amounts to almost EUR 10 million, of which approximately EUR 1.5 million will go to TU Dresden. With the ClonEScape project, TUD is involved in an ERC Synergy Grant for the fourth time. In this funding round, a total of 548 applications were submitted, 57 of which received positive decisions. The ERC Synergy Grant is considered the most prestigious research funding in the EU.

CV:
Prof. Dr.  Dr. med. Daniel Stange studied Medicine in Hamburg and Heidelberg. He received his doctorate in 2006 from the German Cancer Research Center. After obtaining his license to practice medicine, he began his training as a abdominal surgeon at Heidelberg University. Daniel Stange completed his scientific training with a PhD from the Utrecht University in the Netherlands. At the end of 2012, he relocated to Dresden, where he now works as First Senior Physician at the Department of Visceral, Thoracic and Vascular Surgery at TU Dresden's Carl Gustav Carus University Hospital Dresden. He heads the Faculty of Medicine's Surgical Research Laboratory at TU Dresden and runs the Patient-derived Model Unit (PMU) at NCT/UCC Dresden. His scientific focus lies on translational research into gastric and colon carcinomas and the molecular biology of intestinal and gastric stem cells.

Contact:
Anne-Stephanie Vetter
Staff Unit Public Relations of the Carl Gustav Carus Faculty of Medicine of TUD Dresden University of Technology
National Center for Tumor Diseases (NCT/UCC) Dresden
Tel.: +49 351 458 17903
Email: anne-stephanie.vetter@tu-dresden.de

www.tu-dresden.de/med

^{National Center for Tumor Diseases (NCT/UCC) Dresden
The National Center for Tumor Diseases (NCT/UCC) Dresden is a joint institution involving the German Cancer Research Center (German abbreviation: DKFZ), the Faculty of Medicine at TU Dresden, the Carl Gustav Carus University Hospital Dresden and the Helmholtz-Zentrum Dresden-Rossendorf (HZDR). The NCT Dresden is part of NCT, which has further sites in Berlin, Heidelberg, SouthWest (Tübingen-Stuttgart/Ulm), WERA (Würzburg, Erlangen, Regensburg, Augsburg) and West (Essen/Cologne).
The NCT has made it its mission to link research and patient care as closely as possible. It is a long-term collaboration between the German Cancer Research Center (German abbreviation: DKFZ), excellent partners at the university medical center, and other outstanding research partners at various locations in Germany. The NCT aims at translating innovations in cancer research in Germany into studies in a targeted and rapid manner, with the aim of diagnosing and treating cancer while maintaining a high quality of life. In doing so, patients are research partners on an equal footing.
The Dresden center draws on the structures of the University Cancer Center Dresden (UCC), which was founded in 2003 as one of the first Comprehensive Cancer Centers (CCC) in Germany. Since 2007, the Dresden center has repeatedly been awarded the title of “Oncological Center of Excellence” by the German Cancer Aid (German abbreviation: DKH).}