Periodic Reporting for period 4 - FORCE (Imaging the Force of Cancer) Berichtszeitraum: 2020-07-01 bis 2021-07-31 Zusammenfassung vom Kontext und den Gesamtzielen des Projekts “Force, Imaging the Force of Cancer,” is a large-scale Horizon 2020 project, whose aim is to address a fundamental need in planning and monitoring of cancer treatment by measuring the forces active in cancer. The mechanical forces on a primary cancer tumour – such as tumour Interstitial Fluid Pressure (IFP) and Cell Traction Force (CTF) at the tumour border zone – are thought to be key indicators of whether cancer therapy is working as well as the likelihood of the cancer spreading to other organs. However, being able to measure these forces non-invasively is currently not possible but is paramount for therapy planning and evaluating treatment efficacy. While the treatment of primary tumour sites is vital, gauging the metastatic potential for cancer spread is increasingly important for ensuring appropriate therapy is given.The FORCE project will tackle these needs by integrating fundamental developments in engineering and Magnetic Resonance Imaging to develop Magnetic Resonance Force Imaging (MRFI) – a novel non-invasive modality for directly measuring Interstitial Fluid Pressure and cell traction forces. We believe that MRFI derived imaging biomarkers will allow for patient stratification prior to therapy and therapy efficacy control during therapy. This has the potential to result in improved patient outcomes at reduced costs. Clinical trials will be conducted for breast cancer, liver cancer, and brain tumours in three major European clinical centers.The participation of major industrial and pharmaceutical partners in the project accelerates the time to market and encourages a prompt implementation. Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse The aim of this project is to measure the forces exerted by a tumour onto its surroundings and quantify the diagnostic impact of this physical parameter in the domain of oncology for breast cancer, liver cancer, and brain tumours. So far, we have demonstrated in simulations and phantom experiments the feasibility to quantify those forces noninvasively via nonlinear tissue mechanics. Our initial results from breast cancer patients show that those lesions that exhibit the largest pressure do show lymphovascular space invasion. We are currently running a clinical trial in order to confirm this in a larger cohort. If confirmed, this has major impact on patient pathway. A patient that is currently scheduled for tumour surgery would rather first received neoadjuvant chemotherapy if the presence of lymphovascular space invasion were known prior to surgery. Hence, the measurement of tumour forces could have an immediate impact on patient management, which is the aim of this project.The liver cancer trial in Paris has started and we have collected initial datasets from patients with hepatocellular carcinoma. Similarly, the brain cancer trial in Basel & Oslo has started as well. Given the promising initial results in breast cancer trials that showed correlation between lymphatic tumour invasion and elevated pressure, we hope to have enough material by the end of this year (2020) in order to aim for a major publication. At the moment we are working on obtaining enough data to draw final conclusions.Our current hardware solution for MRE has reached a high level of technical and clinical maturity and we are aiming for translation to industry. We achieved a good level of phase stability of the MRE setup which now provides data of the highest quality. We furthermore significantly improved on the reconstruction with remarkable data in the human brain revealing details which had not been visible before. The liver setup has received hardware additions that render the acquisition more patient friendly and we also implemented a single breath hold sequence for comparison with other methods. All new insights equally went into the breast setup in London, which now provides excellent data within 7mins data acquisition time within the normal clinical routine. On the post-processing side, we gained new insight to greatly improve stability and quality. The basic paper about pressure reconstruction has been successful published in Scientific Reports. We also finished the mechano-transduction experiments with very exciting new insight. Caspase7 is generated due to mechanical shear waves. The manuscript will soon go out for review. Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts) Our consortium is tightly working together with significant progress demonstrating the feasibility to measure IFP, quantifying cellular forces fundamentally, validating the impact of IFP in preclinical models and the influence of macroscopic forces on tumor biomechanics, to finally translating the technology into clinical reality by completing clinical trials on breast cancer, liver cancer, and brain cancer. The provision of clinical data will allow us to gauge and further develop the method and bring it from bench to bedside. As three major clinical European centers are tightly involved in this project, main focus is put on the patient benefit generated by the provision of the knowledge regarding the forces generated by a tumor. This involves selection of the drug most likely to work given a certain value of IFP, gauging success of therapy or failure during chemo, and finally predicting whether a tumor has already metastasized towards for instance the sentinel lymph node in case of breast cancer.