FOR 5628:  Multiscale magnetic resonance elastography in cancer: The mechanical niche of tumor formation and metastatic spread – towards an improved diagnosis of cancer through mechanical imaging

• Subject Area: Medicine
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513752256

The mechanical niche of cancer emerges from the collective behavior of cells, which is guided by their physical interactions with extracellular matrix, stromal cells and lymphatic and blood vessels. These mechanosensory signals result in unique material properties not found in inanimate matter and are closely linked to the emergent states of cancer cells in correlation with their aggressiveness and metastatic potential. Multiscale-multifrequency magnetic resonance elastography (mMRE) can quantitatively map material properties of tumors in vivo including tissue stiffness, friction, and fluidity. Here, we propose an interdisciplinary research unit for the study of cancer mechanics to unveil, for the first time, the mechano-physical cascade of carcinogenesis in vivo, to decipher the physical signals that transform dormant tumors into aggressive cancers, to mechanistically understand the properties of tumor niches that promote tumor development, invasive growth, and cancer recurrence after therapy, and to develop diagnostic imaging markers based on mMRE. Covering different length scales, we will sensitize micromechanical test methods and mMRE to disrupted tissue homeostasis, matrix remodeling, and non-equilibrium cellular interactions that collectively shape the mechanical microenvironment in which tumors grow and proliferate. We will combine state-of-the-art biotechnology approaches in organoid cultures and recellularized tissue scaffolds with animal tumor models, micromechanical test methods, metabolic modeling, and multiparametric, quantitative imaging including mMRE in tissue samples and patients to study the multiscale mechanical properties of the cancerogenic niche from microscopic to macroscopic length scales. This approach will allow us to thoroughly test our main hypothesis that in vivo mMRE i) is sensitive to solid-fluid mechanical property changes associated with tumor development, ii) is specific to collective cellular behavior underlying malignant transformation, and iii) predicts the formation of solid stress in carcinogenic niches. Our research plan evolves around three pillars that cover the micro-, meso- and macroscopic ranges of tumor properties. Each pillar combines innovative multiparametric imaging techniques including micromechanical tests and clinical mMRE as well as analyses of transcriptomics, proteomics, cell and nucleus shape and histopathology in both ex vivo specimens and in vivo tissues. We will systematically analyze and combine these multiscale data by viscoelastic modeling of the fundamental properties of cancers across entities and individual tumor stages with the perspective of advancing noninvasive diagnostic imaging by mMRE towards risk stratification of tumor development, aggressiveness, and recurrence after treatment. Ultimately, focusing on in vivo soft tissue mechanics, this research unit is going to tackle the long-standing yet unresolved question of the origin of cancer from the physics perspective.

• DFG Programme: Research Units

Projects

• A01 Cell-microenvironment mechanical interactions in cancer from single cells to tissues (Applicants Huch, Meritxell ;  Taubenberger, Anna )
• B03 Scaffold composition and fluid pressure in recellularized hepatic and pancreatic tumors (Applicants Guo, Jing ;  Hillebrandt, Karl Herbert )
• C01 Multiscale mechanical properties of tumors and tumor environment – from tissue specimens to patients (Applicants Marticorena Garcia, Stephan ;  Sauer, Igor Maximilian )
• C02 Wideband dispersion mMRE for the detection of tissue fluidity in precancerous niches (Applicants Reiter, Rolf Otto ;  Sack, Ingolf )
• C03 Predictive mechanical tumor markers: solid stress and multiscale viscoelastic data analysis (Applicants Guo, Jing ;  Sack, Ingolf )
• Cancer cell unjamming and jamming as prerequisite for the formation of primary and metastatic tumors (Applicants Käs, Josef Alfons ;  Sauer, Igor Maximilian )
• Coordination Funds (Applicant Sack, Ingolf )
• Interplay of mechanical properties of tissue microenvironment, oncogenic signaling, and metabolism in hepatopancreatic cancer (Applicants Berndt, Nikolaus ;  Sers, Christine )
• Neuroblastoma as pediatric tumor model: in vivo mechanical niches in zebrafish and patients (Applicants Eggert, Angelika ;  Heeren-Hagemann, Anja )
• Role of tissue mechanical and metabolic properties in cancer formation studied in a translational liver tumor model (Applicants Guo, Jing ;  Savic, Lynn Jeanette )

• Spokesperson: Professor Dr. Ingolf Sack